neurodegenerative diseases (13 mb )

Biofiles Volume 7 Number 2

Neurodegenerative DiseasesAlzheimers Disease

Huntingtons Disease

Parkinsons Disease

Biofilescontents

Introduction 3

Alzheimers Disease Antibodies Proteins Peptides and Assays 4

Huntingtons Disease Antibodies Proteins and Peptides 9

Parkinsons Disease Antibodies Proteins and Peptides 16

Differential protein expression in rat models using the Panoramareg Neurobiology Array 21

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sigmacombiofiles

Highlights from this issue This issue of Biofiles highlights current

research in the areas of Alzheimerrsquos Parkinsonrsquos and Huntingtonrsquos disease

as representative of major efforts to delineate key events in the development

of neurodegenerative diseases Neurodegenerative diseases affect the central nervous system causing

progressive nervous system dysfunction These debilitating and incurable conditions are characterized by loss of neuronal cell function

and are often associated with atrophy of the affected nervous system structures Products featured in this issue include antibodies proteins peptides and assays which represent a broader set of tools offered to

support basic research in neurodegenerative disease

Coming next issue The next issue of Biofiles highlights Epigenetics the study of stable but

potentially reversible alterations in gene expression that occur

without permanent changes in DNA sequence The significance of epigenetic

changes in the development of cancer autism and other diseases is being increasingly recognized Given this developing mechanistic

understanding the field is attracting investigators interested in diverse aspects of chromatin and chromosome biology

Technical contentCarolyn L CrankshawProduct Specialistcarolyncrankshawsialcom

Dr Eliezer KopfManager Manufacturing eliezerkopfsialcom

Order sigmacomorder Technical service sigmacomtechinfo sigmacomlifescience 3

Neurodegenerative diseases affect the central nervous system causing progressive nervous system dysfunction These debilitating and incurable conditions are characterized by loss of neuronal cell function and are often associated with atrophy of the affected nervous system structures An important subset of neurodegenerative disease concerns dementias associated with aging Alzheimers disease (AD) is the most common clinically recognized dementia in aging populations and 43 of people 85 or older are thought to suffer from Alzheimers in the United States Parkinsons disease (PD) another common nervous system disorder associated with the elderly affects 1-3 of the population over 60 United Nations population projections estimate a world population of 400 million people 80 years of age or older by the year 2050 Given the financial societal and personal impact of the burden of these diseases determining causes prevention and treatment has become a major focus of basic and clinical research

Study of the etiology of neurodegenerative diseases shows association with genetic factors to be variable within populations for one disease state Even in the case of Huntingtons disease (HD) which is linked to a specific gene how mutant Huntingtins protein effects downstream symptoms of the disorder including dementia is not fully understood The molecular basis of the effects of genetic variation lifestyle and environmental factors including trauma and infection involves multiple signaling pathways Neuropathological hallmarks of dementia include β-amyloid plaques and

neurofibrillary tangles in AD and Lewy body inclusions in PD However while protein aggregation clearly plays a role in neurodegenerative disease there is evidence these are signatures of neuronal damage and additional causative elements remain to be discerned The role of inflammation is an active area of investigation as is the role of nitric oxide signaling The effects of these and other key events on transcriptional regulation and initiation of apoptosis and neurotoxicity continues to be intensively explored

This brochure highlights current understanding in the areas of Alzheimers disease Parkinsons disease and Huntingtons disease as representative of major research efforts to delineate key events in the development of neurodegenerative diseases The associated products represent a broader set of tools offered to support basic research in neurodegenerative disease and in neuroscience

References1 Alzheimers Disease Fact and Figures Alzheimers

Association 2008 httpwwwalzorgdownloadsFacts_Figures_2011pdf

2 Wright WA Geographic and ethnic variation in Parkin-son disease a population-based study of US Medicare beneficiaries Neuroepidemiology 2010 24 143-151

3 Holmes C et al Long-term effects of Aszlig42 immunisation in Alzheimers disease follow-up of a randomised placebo-controlled phase I trial Lancet 2008 372 216-23

4 Griffin WST Inflammation and neurodegenerative disease Am J Clin Nutr 2006 83 472S-474S

5 Breitner JC et al Extended results of the Alzheimers disease anti-inflammatory prevention trial Alzheimers Dement 2011 7 402-11

6 Zhang L et al Role of nitric oxide in Parkinsons disease Pharmacol Ther 2006 109 33-41

IntroductionCarolyn L CrankshawProduct Specialistcarolyncrankshawsialcom

4

Alzheimers Disease Antibodies Proteins Peptides and Assays

Alzheimerprimes Disease

Alzheimers disease (AD) is the most common cause of dementia in the elderly and is characterized by gradual loss of cognitive functions Hallmark pathohistological findings of AD include widespread neuronal degeneration extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT) Biochemical changes affecting multiple pathways contribute to AD pathology Hyperphosphorylation of Tau (MAPT) causes aggregation contributing to the formation of NFT The protein product of DOCK3 stimulates Tau phosphorylation and also interacts with presenilin proteins components of the γ-secretase complex involved in processing of the amyloid β precursor protein (APP) Genetic and biochemical data support the hypothesis that amyloid-β (Aβ) accumulation and aggregation in the brain contribute to the pathogenesis of AD Aβ is derived from sequential proteolytic processing of APP by β-secretases (BACE1 BACE2) and the γ-secretase complex (APH1 NCSTN PSEN1 PSEN2 PSENEN) The longer Aβ42 form has a higher tendency to aggregate and is more toxic than the shorter Aβ40 form A common feature of most Familial Alzheimers Disease (FAD) mutations is an increase in the generation of Aβ peptides particularly Aβ42 Mutations associated with early-onset FAD are found in the APP gene itself or in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes Another gene associated with early-onset FAD TMED10 encodes a protein which regulates γ-secretase activity Ubiquilin

a ubiquitin-like protein interacts with presenilin-2 and is believed to promote presenilin protein accumulation

FAD genetics and mouse models have shed light on early-onset AD pathogenesis but the vast majority of AD cases occur late in life The 4 allele of the apolipoprotein E (APOE) gene (ApoE e4 variant) is a major risk for late-onset AD (LOAD) compared to the APOE2 and APOE3 variants ApoE mediates binding internalization and catabolism of lipoprotein particles via

interaction with members of the low density lipoprotein receptor (LDLR) family The prototype of this family LDLR has a major role maintaining cholesterol homeostasis ApoE receptors include LDLR LDL receptor related proteins (LRP1 LRP1B LRP2) apoE receptor 2 (ApoER2) and the very low density lipoprotein receptor (VLDLR) The basic functions of apoE in normal brain and the role of apoE in neurodegenerative disease remain unknown It is thought the full length and soluble forms of the

Extracellular Space

Cytoplasm

Amyloid-β

Senile plaque Oxidative stress

Lipidperoxidation

Membranedamage

Neuronal death

Neurobrillarytangles

Destabilizedmicrotubules

Impairedaxonal transport

Membranedamage

Hyperphosphorylated

destabilization ofneuronal calcium levels

P

TAU

p35

p25

CDK5

ERK12

CK12

p38 MAPK

PKA

PKCε

MARK

neCa2+

γ-secretase

β-secretase

AKTCDK5

GSK-3β

Calpain

X

γ-secretase

β-secretase

TAU

CalpChemicalDrug or Toxicant

Cytokine or Growth Factor

Enzyme

G-proteinCoupledReceptor

Group orComplex

Ion Channel

Kinase

Phosphorylated Protein

OxidizedProtein

Ligand-dependent NuclearReceptor

microRNA

Peptidase

Phosphatase

TranscriptionRegulator

TranslationRegulator

TransmembraneReceptor

Transporter

Other

Key

Note ldquoActs Onrdquo and ldquoInhibitsrdquo edge may also include a binding event

Direct Interaction

Indirect Interaction

A B Bindings Only

A B Inhibits

A B Inhibits and Acts On

A B Leads To

A B Translocates To

A B Reaction

A B

A B

Enzyme Catalysis Reaction

Disruption

Mutated Gene

A B Acts On

iT

xicant

r c

microRN

a

a

r ct a

h

tor Peptida

Phosph

Kinase

ndenleaep

Phosh

LigadepeNucRece

el

ipio

io

Transme

riTranscriitoRegulat

tTranslatRegulatoRegulat

T

TranscriRegulatTranscr

lated

t

o

Mutated

Transpo

Other

P

O

Alzheimers Disease Amyloid Processing For this and related interactive pathways see sigmacomadsig


apoE receptors alter APP processing and Aβ clearance thus contributing to AD pathogenesis Seladin-1 (DHCR24) a crucial enzyme involved in sterol synthesis is downregulated in regions of the brain affected by AD

Another focus in AD research centers around inflammation Patients who have succumbed to Alzheimers show overexpression of interleukin-1 (IL1A) and the soluble astrocyte inflammatory cytokine S100B Further IL1 induces Tau expression and phosphorylation in rat brain and staining brain sections from Alzheimers patients reveals abundant MAPK1 in the same regions as hyperphosphorylated Tau The contribution of these and other events to the pathophysiology and progression of AD continues to be actively investigated

References1 Griffin WST Inflammation and neurodegenerative

disease Am J Clin Nutr 2006 83 472S-474S2 Li Y et al Interleukin-1 mediates pathological effects

of microglia on tau phosphrylation and on synaptophysin

synthesis in cortical neurons through a p38-MAPK pathway J Neurosci 2003 23 1605-11

3 Griffin WST et al Interleukin-1 mediates Alzheimer and Lewy body pathologies J Neuroinflammation 2006 3 5

4 Goldgaber D et al Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimers disease Science 1987 235 877-880

5 Kang J et al The precursor of Alzheimers disease amyloid A4 protein resembles a cell surface receptor Nature 1987 325 733-736

6 Tanzi R et al Amyloid beta protein gene cDNA mRNA distribution and genetic linkage near the Alzheimer locus Science 1987 235 880-884

7 Tanaka S et al Tissue-specific expression of three types of beta-protein precursor mRNA enhancement of protease inhibitor-harboring types in Alzheimers disease brain Biochem Biophys Res Commun 1989 165 1406-1414

8 Haass C and Selkoe DJ Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide Cell 1993 75 1039-1042

9 Vassar R Beta-secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999 286 735-741

10 Yan R et al Membrane-anchored aspartyl protease with Alzheimers disease beta-secretase activity Nature 1999 402 533-537

11 Sinha S et al Purification and cloning of amyloid precursor protein beta-secretase from human brain Nature 1999 402 537-540

12 Price DL and Sisodia SS Mutant genes in familial Alzheimers disease and transgenic models Ann Rev Neurosci 1998 21 479-505

13 Tanzi RE et al The Presenilin genes and their role in early-onset familial Alzheimers disease Alzheimers Disease Rev 1996 1 91-98

14 Schellenberg GD et al Genetic linkage evidence for a familial Alzheimers disease locus on chromosome 14 Science 1992 258 668-671

15 Maroteaux L and Scheller RH The rat brain synucleins family of proteins transiently associated with neuronal membrane Mol Brain Res 1991 11 335-343

16 Ueda K et al Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease Proc Natl Acad Sci USA 1993 90 11282-11286

17 Yu G et al Nicastrin modulates presenilin-mediated notchglp-1 signal transduction and betaAPP processing Nature 2000 407 48-54

18 Schenk D et al Alzheimers disease A partner for presenilin Nature 2000 407 34-35

19 Sisodia SS Neuroscience An accomplice for gamma-secretase brought into focus Science 2000 289 2296-2297

20 Usdin TB et al Molecular biology of the vesicular ACh transporter Trends Neurosci 1995 18 218-224

21 Varoqui H and Erickson JD The cytoplasmic tail of the vesicular acetylcholine transporter contains a synaptic vesicle targeting signal J Biol Chem 1998 273 9094-9098

Antibodies for Alzheimerprimes ResearchProduct Name Host Clone No Gene Symbol Species Reactivity Application Array Antibody Cat NoMonoclonal Anti-β-Amyloid mouse BAM-10 APP human human ELISA (i)

IHC (p)WB

A3981-25ULA3981-200UL

Monoclonal Anti-β-Amyloid mouse BAM-10 APP human human ELISA (i)IHC (p)

- A5213-2ML

Anti-APH1A goat - APH1A human humanmouse

rat

ELISA (i)WB

- SAB2500076-100UG

Anti-ApoER2 rabbit - LRP8 human human WB A3481-25ULA3481-200UL

Monoclonal Anti-Apolipoprotein E mouse E6D7 APOE human human ELISA (i)IHCIP

WB

A8599-100UL

Anti-BACE 1 N-Terminus (46-62) rabbit - BACE1 human human WB B0681-2ML

Anti-BACE-2 N-terminus (43-60) rabbit - BACE2 human human IF (i)WB

- B7935-200UL

Anti-m-Calpain (Domain III) Large Subunit

rabbit - Capn3 mouseCAPN3 human

Capn3 rat

humanmouse

rat

WB - C0728-1MG

Anti-Glycogen Synthase Kinase-3β (GSK-3β)

rabbit - GSK3B humanGsk3b rat

humanrat

ARRWB

- G7914-2ML

Anti-LRP1 (C-terminal) rabbit - Lrp1 mouseLRP1 human

Lrp1 rat

humanmouse

rat

IF (i)WBWB

L2170-25ULL2170-200UL

Anti-LRP6 (C-terminal region) rabbit - Lrp6 mouseLRP6 human

human IPWB

L2045-25ULL2045-200UL

Checkmark denotes antibodies represented on the Panoramareg Neurobiology Microarray

6

Product Name Host Clone No Gene Symbol Species Reactivity Application Array Antibody Cat NoMonoclonal Anti-MAP Kinase Activated (Diphosphorylated ERK-1amp2)

mouse MAPK-YT Mapk3 ratMAPK1 humanMapk3 mouseMapk1 mouse

Mapk1 ratMAPK3 human

Caenorhabditis elegansDrosophila

Xenopusbovine

hamsterhumanmouse

ratyeast

ELISA (i)ICC

IHC (p)IP

WB

- M8159-2ML

Monoclonal Anti-MAP Kinase Activated (Diphosphorylated ERK-1amp2)

mouse MAPK-YT Mapk1 mouseMAPK3 human

Mapk3 ratMapk3 mouse



Xenopusbovine

hamsterhumanmouse

ratyeast

ARRELISA (i)

ICCIHC (p)

IPWB

M9692-200UL

Anti-Nicastrin rabbit - NCSTN human humanmouse

rat

ARRIF (i)

IPWB

N1660-2ML

Anti-p35 (Cdk5 Regulator) rabbit - CDK5R1 humanCdk5r1 rat

humanrat

ARRWB

- P9489-2ML

Anti-Pen-2 rabbit - Psen2 mousePSENEN human

human ARRWB

P5622-200UL

Anti-phospho-PKB (pSer473) rabbit - AKT1 humanAkt1 rat

Akt1 mouse

mouserat

ARRWB

- P4112-2ML

Anti-Presenilin-1 (S182) rabbit - Psen1 mousePsen1 rat

PSEN1 human

Xenopushumanmouse

rat

ARRIHC (p)

WB

P7854-2ML

Anti-Seladin-1 rabbit - DHCR24 human human WB S8571-200UL

Anti-τ (Tau) rabbit - MAPT human chickenwide range

WB T6402-2MLT6402-1ML

Monoclonal Anti-τ (Tau) mouse TAU-2 MAPT human bovinechickenhumanmonkey

ARRIHC (p)

WB

T5530-2MLT5530-5ML

Anti-TMP21 (C-terminal) rabbit - TMED10 humanTmed10 rat

Tmed10 mouse

humanmouse

rat

WB T3827-25ULT3827-200UL

Anti-Ubiquilin-1 rabbit - UBQLN1 human human WB U7258-25ULU7258-200UL

Monoclonal Anti-Vimentin mouse LN-6 Vim ratVim mouseVIM human

bovinefeline

humanmouse

pigrabbit

ratsheep

IF (i)IHC (p)

IPWB

- V2258-2MLV2258-5ML


Antibodies for Alzheimerprimes Research continued


Proteins amp Peptides for Alzheimerprimes Research Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No

AKT2 active GST tagged human

AKT2 is a serinethreonine kinase that functions in cellular signaling pathways regulating glucose metabolism transcription survival cell proliferation angiogenesis and cell motility

AKT2 ge70 SDS-PAGE A2233-10UG

Amyloid Precursor Protein α Secreted human

αminussecretase-cleaved soluble amyloid precursor protein has been shown to have neuroprotective properties Several G protein-coupled receptors are known to activate α-secretase-dependent processing of APP

APP gt90 SDS-PAGE S9564-25UG

Amyloid Precursor Protein β Secreted human

Proteolytic cleavage product of amyloid β precursor protein (APP) sAPPβ is thought to modulate neuronal function and cell survival


Amyloid β Protein Fragment 1-40

β-Amyloid fragment that is neurotoxic in vivo and in vitro in neuronal cell cultures

APP ge90 HPLC A1075-1MGA1075-5MG


The predominant fragment of amyloid β-protein in Alzheimers disease APP ge95 HPLC A9810-1MG


Functional domain of Aβ required for both neurotrophic and neurotoxic effects

APP ge97 HPLC A4559-250UGA4559-1MG

Amyloid β Protein Fragment 1-40 All D-Amino Acids

This D-amino acid peptide functions as a control useful in elucidating structural dependence of aggregation properties characteristic of the amyloid β 1-40 peptide associated with plaque formation and Alzheimers disease

APP gt70 HPLC A5973-5MG

Apolipoprotein E4 human The ApoE4 isoform of ApoE correlates with increased incidence of Alzheimers disease and has been shown to regulate lipid metabolism and bind amyloid β Recombinant ApoE4 retains full biological activity and can be used to study interactions of ApoE4 with amyloid-β Tau and LDLR

APOE ge90 SDS-PAGE and HPLC

A3234-100UG

CDK5p25 active GST tagged human

CDK5 abundant in the mammalian brain is activated upon binding to neuronal protein p35 CDK5p35 breakdown to CDK5p25 is associated with increased neurotoxicity as well as neurodegenerative diseases including Alzheimers and Parkinsons

CDK5CDK5R1

ge70 SDS-PAGE C0745-10UG

ERK1 active untagged human

ERK1 (MAPK3) participates in cellular signaling cascades that are activated in response to numerous growth factors and cytokines Disruption of MAP kinase signaling functionality is associated with disease states including inflammation cancer and neurodegenerative disease

MAPK3 ge70 SDS-PAGE E7407-10UG

ERK2 active GST tagged human



Imna(--) mouse embryonic fibroblasts stained with Monoclonal Anti-Vimentin clone LN-6 (Cat No V2258)

From Shyam Khatau Department of Chemical and Biomolecular Engineering Johns Hopkins University Baltimore MD

Drosophila wing imaginal disc (500 micrometers long) was stained with Monoclonal Anti-MAP Kinase Activated (Cat No M8159)

From L Gabay R Seger B-Z Shilo Weizmann Institute of Science ehovot Israel reproduced cover photograph from Science 277 1103 (1997) Used with permission

8

Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No GSK3β active

His tagged humanGSK3B a serinethreonine kinase functions in physiological processes including the control of glycogen metabolism cell division proliferation motility and survival Current evidence indicates GSK3B plays a role in neurological disease and it is known to phosphorylate both Tau and presenilin-1

GSK3B ge70 SDS-PAGE G4296-10UG

Presenilin-1 N-Terminal Peptide

Used to study production of Aβ[X-42] peptide and accumulation of endogenous presenilin

PSEN1 ge50 HPLC P2490-1MG


Product used to study production of Aβ[X-42] peptide and accumulation of endogenous presenilin


Protein Kinase A Catalytic Subunit β Active human

A catalytic subunit of cAMP-dependent protein kinase the protein encoded by PRKACB catalyzes events downstream of GPCRs including cell cycle differentiation and proliferation When activated this subunit acts on metabolic enzymes ion channels and transcription factors such as CREB

PRKACB ge85 SDS-PAGE P6998-5UG

β-Secretase human Transmembrane protease responsible for the β site cleavage of the amyloid precursor protein (APP) to produce amyloid β peptide

BACE1 ge90 SDS-PAGE S4195-50UG

Tau-352 human Isoform of Tau variant 0N3R having 3 microtubule binding repeats (R) and no amino terminal inserts (N)

MAPT ge90 SDS-PAGE T9950-50UG

Tau-412 human Isoform of Tau variant 1N4R having 4 microtubule binding repeats (R) and one amino terminal insert (N)


Tau-441 human Isoform of Tau variant 2N4R having 4 microtubule binding repeats (R) and 2 amino terminal inserts (N)


8 Vimentin His tagged human

Vimentin is a member of the intermediate filament family of proteins that plays a significant role in supporting and anchoring organelles in the cytosol It functions to maintain cell shape and stabilize cytoskeletal interactions

VIM ge90 SDS-PAGE SRP5150-50UG

Assays for Alzheimerprimes ResearchBACE-1 Activity Assay

Product Name Application Cat NoSensiZyme BACE1 Activity Assay Kit sufficient for 96 multiwell tests

The BACE1 Activity Assay Kit provides all the reagents required for highly sensitive detection of BACE1 activity in cell extracts cell culture media tissue extracts and purified enzyme preparations and also for inhibitor screening This assay is both sensitive and specific The enhanced sensitivity is achieved by the signal amplification via the chain reaction The specificity is achieved by both the immunochemical isolation of the BACE1 enzyme from the extract by specific antibodies bound to the 96-well plate and the use of an enzyme substrate (Substrate A) containing a BACE1 specific cleavage site

CS1060-1KT

β-Secretase (BACE1) Activity Detection Kit (Fluorescent) 1 kit sufficient for 250 reactions

The kit provides all the reagents required for an efficient detection of BACE1 activity It contains an enzyme to be used for screening of potential BACE1 inhibitors The assay is based on the fluorescence resonance energy transfer (FRET) method in which the fluorescence signal enhancement is observed after substrate cleavage by BACE1

CS0010-1KT

To view additional products for Alzheimers Disease Research visit sigmacomalz

Proteins amp Peptides for Alzheimerprimes Research continued


Huntingtons disease (HD) is an autosomal dominant late-onset neurodegenerative disorder characterized by a selective neuronal cell death in the cortex and striatum leading to cognitive dysfunction motor impairment and behavioral changes The underlying cause of HD is the expansion of a CAG repeat located within the first exon of the Huntingtin gene (HTT) In persons with HD the HTT gene is found to contain 36 or more CAG repeats resulting in a mutant form of the Huntingtin protein The current hypothesis in HD is that neuronal degeneration results from the combined effects of a gain-of-function in the mutated form of HTT along with a loss of function in the wild-type HTT Pathogenesis in HD appears to involve different mechanisms

1 HD mutation is translated into an expanded polyglutamine tract (polyQ) that induces conformational changes and abnormal folding in the mutated Huntingtin These insoluble proteins accumulate as ubiquitinated cytoplasmic perinuclear aggregates The resulting perinuclear inclusions impair the ubiquitin-proteasome system leading to the accumulation of more misfolded proteins and cell death

2 HTT mutation results in abnormal protein interactions For example mutant Huntingtin interferes with the binding of disks large associated protein 4 (DLGAP4) to the glutamate receptor NMDAR1 (GRIN1) This results in receptor hypersensitivity an influx of Ca2+ and excitotoxicity Additionally increased Ca2+ levels activate caspases leading to cell apoptosis cleavage of mutant Huntingtin and the generation of toxic N-terminal fragments In HD mutant Huntingtin can also inhibit transcription by failing to bind

to the repressor REST in the cytoplasm This results in an accumulation of the repressor in the nucleus and inhibition of brain-derived neurotrophic factor (BDNF) transcription which is an important survival factor for striatal neurons Finally decreased binding between mutant Huntingtin and proteins such as MLK2 (MAP3K10) HIP1 and HIP14 leads to apoptotic cell death impaired vesicle trafficking and endocytosis

3 Huntingtin mutation leads to aggregate sequestration of various proteins including transcription factors Proteolytically cleaved N-terminal fragments of mutated Huntingtin can translocate into the nucleus to form neuronal intranuclear inclusions Once there mutated Huntingtin recruits transcription factors such as CBP (CREBBP EP300) TBP and SIN3A which disrupt gene transcription leading to neurodegeneration

References1 Hu Y et al Bcl-XL interacts with Apaf-1 and inhibits

Apaf-1-dependent caspase-9 activation Proc Natl Acad Sci USA 1998 95 4386-4391

2 Rangone H et al The serum- and glucocorticoid- induced kinase SGK inhibits mutant Huntingtin-induced toxicity by phosphorylating serine 421 of Huntingtin Eur J Neurosci 2004 19 273-279

3 Nakagawa T and Yuan J Cross-talk between two cysteine protease families Activation of caspase-12 by calpain in apoptosis J Cell Biol 2000 150 887-894

4 Heumann R et al Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration J Cell Biol 2000 151 1537-1548

5 Weber MM et al Rat somatotroph insulin-like growth factor-II (IGF-II) signaling role of the IGF-I receptor Endocrinology 1992 131 2147-2153

6 Liu YF et al SH3 domain-dependent association of Huntingtin with epidermal growth factor receptor signaling complexes J Biol Chem 1997 272 8121-8124

7 Perkins CL et al The role of Apaf-1 caspase-9 and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis Cancer Res 2000 60 1645-1653

8 Tartare-Deckert S et al Interaction of the molecular

weight 85K regulatory subunit of the phosphatidylino-sitol 3-kinase with the insulin receptor and the insulin-like growth factor-1 (IGF- I) receptor comparative study using the yeast two-hybrid system Endocrinology 1996 137 1019-1024

9 Doonan F et al Caspase-Independent Photoreceptor Apoptosis in Mouse Models of Retinal Degeneration J Neurosci 2003 23 5723-5731

10 Liu YF et al Activation of MLK2-mediated signaling cascades by polyglutamine-expanded Huntingtin J Biol Chem 2000 275 19035-19040

11 Borg JP et al The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein Mol Cell Biol 1996 16 6229-6241

12 Petrosillo G et al Ca2+-induced Reactive Oxygen Species Production Promotes Cytochrome c Release from Rat Liver Mitochondria via Mitochondrial Permeability Transition (MPT)-dependent and MPT-independent Mechanisms role of cardiolipin J Biol Chem 2004 279 53103-53108

13 Adler V et al Complexes of p21RAS with JUN N-terminal kinase and JUN proteins Proc Natl Acad Sci USA 1995 92 10585-10589

14 Thien CB and Langdon WY Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl Oncogene 1997 15 2909-2919

15 Yazgan O and Pfarr CM Regulation of two JunD isoforms by Jun-N-terminal kinases J Biol Chem 2002 277 29710-29718

16 Hirai S et al MSTMLK2 a member of the mixed lineage kinase family directly phosphorylates and activates SEK1 an activator of c-Jun N-terminal kinasestress-activated protein kinase J Biol Chem 1997 272 15167-15173

17 Hattori S et al Activation of mitogen-activated protein kinase and its activator by ras in intact cells and in a cell-free system J Biol Chem 1992 267 20346-20351

18 Montcouquiol M and Corwin JT Intracellular signals that control cell proliferation in mammalian balance epithelia key roles for phosphatidylinositol-3 kinase mammalian target of rapamycin and S6 kinases in preference to calcium protein kinase C and mitogen-activated protein kinase J Neurosci 2001 21 570-580

19 Juliano RL Signal transduction by cell adhesion receptors and the cytoskeleton functions of integrins cadherins selectins and immunoglobulin-superfamily members Annu Rev Pharmacol Toxicol 2002 42 283-323

20 Rosales JL et al GTP-dependent secretion from neutrophils is regulated by Cdk5 J Biol Chem 2004 279 53932-53936

21 Shibuya M Structure and function of VEGFVEGF-receptor system involved in angiogenesis Cell Struct Funct 2001 26 25-35

22 Gafni J et al Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity accumulation of calpaincaspase fragments in the nucleus J Biol Chem 2004 279 20211-20220

Huntingtons Disease Antibodies Proteins and Peptides

Huntingtons Disease

10

Huntingtons Disease Signaling For this and related interactive pathways see sigmacomhdsig

Gene Transcription

Cell SurvivalNeurodegeneration

Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+

GRIN2BCa2+ ChannelN-type

GRM15

Caspas

Ca2+

Ca2+

DecreasedMitochondrial

Membrane PotentialExcitotoxic Death Apoptosis

Neurodegeneration

HD

Bax

HD

NeuronalIntranuclear

Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD

HD NH2-TerminalFragment Aggregates



HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1

HD NH2-TerminalFragment Aggggregates

DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33

HD FraHD Fraaaaaagmagmmeme

TAFII130

CBP HDFragment

TAFII130TA H0AFII130

TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription

EnkaphalinEnkaphalin

HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A

Reduced in HD Reduced in HD

SynapticVesicle

1

HDD SH3GL3 HDPACSIN1 HPACCSIN1

n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A


Growth andDierentiation

bull Neurite Outgrowth bull Survival bull Proliferation bull Differentiation

EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF

EGFR EGFR EGFR EGFR TRKA TRKA

HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription

NeuronalDevelopment and

SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE

PerinuclearInclusions

Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD

Axonal TransportAlong Microtubules

NeurotoxicityDeath

MitochondrialTracking

MitochondrialDysfunction

HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2

MisfDDHHHDHDdedfoold

TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2

Chemical Drug orToxicant


Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe

P Ubiquitinated Protein

Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12

Antibodies for Huntingtons ResearchProduct Name Host Clone No Gene Symbol Species Reactivity Application Array Antibody Cat NoMonoclonal Anti-BDNF mouse 1B10 BDNF human human ELISA (i)

WB- SAB1402127-100UG

Monoclonal Anti-CREBBP mouse 2B6 CREBBP human human ELISA (c)ELISA (i)

WB

- SAB1403694-100UG

Anti-DLGAP2 rabbit - DLGAP2 human human IHC (p)PAWB

- HPA030320-100UL

Anti-EP300 rabbit - EP300 human human IF (i)IHC (p)

PA

- HPA003128-100UL

Anti-Glutamate Receptor NMDAR1 (NR1)

rabbit - GRIN1 humanGrin1 rat

Grin1 mouse

humanmouse

rat

WB - G8913-2ML

Anti-HAP1 (C-terminal) rabbit - HAP1 human human WB - SAB4200293-200UL

Anti-HIP1 rabbit - HIP1 human human IF (i)IHC (p)

PAWB

- HPA013606-100UL

Anti-HIP14 rabbit - Zdhhc17 mouseZDHHC17 human

bovinecaninehumanmouse

rat

WB H7414-25ULH7414-200UL

Monoclonal Anti-Histone Deacetylase 1 (HDAC1)

mouse HDAC1-21 Hdac1 mouseHDAC1 human

humanmouse

ARRELISA (i)

IPWB

- H6287-200UL


mouse HDAC2-62 HDAC2 humanHdac2 mouse

Hdac2 rat

bovinecaninechickenhumanmouse

rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL


mouse HDAC4-144 Hdac4 ratHDAC4 humanHdac4 mouse

humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL

Anti-MAP3K10 (867-880) rabbit - MAP3K10 human human WB - M6571-200UL

Anti-MAPK9 (276-290) rabbit - MAPK9 human human WB - M7573-200UL

Anti-NeuroD1 rabbit - NEUROD1 humanNeurod1 rat

Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL

Monoclonal Anti-Polyglutamines mouse 3B5H10 HTT human human ICCIP

WB

P1874-200UL

Anti-REST rabbit - REST human human IF (i)IHC (p)

PA

- HPA006079-100UL

Anti-Sin3A C-Terminal rabbit - Sin3a ratSIN3A humanSin3a mouse

human ARRIP

WB

- S6695-200UL

Monoclonal Anti-TBP mouse 58C9 Tbp Drosophila melanogasterTBP human

Drosophila melanogasterSf9 cell line

humanyeast

IPWB

- T1827-25ULT1827-200UL


Immunofluorescence of HUVEC cells using MAP3K10 (867-880) (RB) Cat No M6571 Yale HTCB IF procedure used

Anti-REST Cat No HPA006079 Immunofluorescent staining of human cell line U-2 OS

Proteins amp Peptides for Huntingtonprimes Research Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No

8 Bcl-xL Active human BCL2L1 is a member of the BCL2 apoptotic regulators that interacts with the voltage-dependent anion channel VDAC The long isoform inhibits apoptosis whereas the short isoform promotes cell death Human Bcl-xL (amino-acids 1-212) GenBank Accession No Z23115 with C-terminal His tag MW = 28 kDa expressed in an E coli expression system

BCL2L1 ge90 SDS-PAGE SRP0187-100UG

8 BDNF human BDNF is a member of the NGF family of neurotrophic growth factors that supports neuron proliferation and survival Expression is reduced in both Huntingtons and Alzheimers disease

BDNF ge98 HPLCge98 SDS-PAGE

SRP3014-10UG

8 Calpain 1 human Cytosolic protease with involvement in cytoskeletal remodeling autophagy and apoptosis as an upstream regulator

CAPN1 ge95 SDS-PAGE C6108-100UG

8 CBP (1319-1710) GST tagged human

CREB-binding protein (CREBBP) binds specifically to phosphorylated CREB enhancing cAMP-responsive transcriptional activity 1319-1710 contains the catalytic domain for lysine acetylation activity

CREBBP ge70 SDS-PAGE SRP5173-50UG

8 KAT3A (518-1207) GST tagged human

KAT3A (CREBBP) mediates coactivation of many transcription factors It couples chromatin remodeling to transcription factor recognition via its intrinsic acetyltransferase activity playing a key role in development and growth control


8 CoREST human Human recombinant CoREST GenBank Accession No NM_015156 amino acids 305-end with N-terminal His tag MW = 20 kDa expressed in E coli expression system

RCOR1 ge60 SDS-PAGE SRP0124-100UG

8 HDAC-1 human Useful for the study of enzyme kinetics and screening inhibitors Human HDAC1 GenBank Accession No NM_004964 full length with C-terminal HIS-DDDDK tag (FLAGreg) and C-terminal His-tag MW = 56 kDa expressed in baculovirus expression system

HDAC1 ge50 SDS-PAGE SRP0100-50UG

8 HDAC-2 His tag human Human HDAC2 GenBank Accession No Q92769 full length with C-terminal His tag MW = 60 kDa expressed in baculovirus expression system


8 HDAC-2 FLAG tag human Human HDAC2 GenBank Accession No Q92769 full length with C-terminal DDDDK tag (FLAGreg) MW = 60 kDa expressed in baculovirus expression system


8 HDAC-4 human Human HDAC4 GenBank Accession No NM_006037 amino acids 627-1085 with N-terminal ST tag MW = 752 kDa expressed in baculovirus expression system


8 HDAC-5 full length human Human HDAC5 GenBank Accession No NM_001015053 full length with N-terminal ST tag MW = 150 kDa expressed in baculovirus expression system


8 HDAC-5 human Human HDAC5 catalytic domain GenBank Accession No NM_001015053 amino acid 657-1123 with C-terminal His tag MW = 51 kDa expressed in baculovirus expression system


IGF-I from rat IGF-I is a member of a family of polypeptide growth factors that mediate growth and development IGF-I has been linked to neuroplasticity and hippocampal neurogenesis IGF-I (Insulin-like Growth Factor-I) is a polypeptide growth factor that stimulates the proliferation of a wide range of cell types including muscle bone and cartilage tissue Rat IGF-I is a 769 kDa protein containing 70 amino acid residues

Igf1 ge95 HPLCge95 SDS-PAGE

SRP4121-20UG

14

Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No Insulin-like Growth Factor-I

humanIGF-I also known as somatomedin C mediates the growth-promoting activity of GH (growth hormone) IGF-I induces endothelial cell migration and is involved in the regulation of angiogenesis IGF-I exerts its actions through the IGF-I receptor

IGF1 ge97 SDS-PAGE or HPLC

I3769-50UG

Insulin-like Growth Factor-I from mouse

Potent mitogenic growth factor that mediates the growth-promoting activities of growth hormone postnatally Mouse and human IGF-I share 97 sequence identity

Igf1 gt97 SDS-PAGE I8779-50UG

Insulin-like Growth Factor-I (E3R) human

IGF1(3R) contains the amino acid substitution E3R which decreases binding to IGF-binding proteins IGF1(3R) therefore is much more potent than the native IFG1

IGF1 gt95 HPLC I2656-25UG

IGF1R (960-end) active His tagged human

IGF1R is a transmembrane tyrosine kinase receptor that mediates the effects of IGF1 and thus plays an important role in growth and development including cerebellar development and hippocampal neuronal plasticity

IGF1R ge70 SDS-PAGE I0786-10UG

Insulin-like Growth Factor-I Receptor human

Binds IGF-I with high affinity IGF-II with lower affinity and insulin with weak affinity


8 JNK2 active GST tagged human

JNK2 (MAPK9) acts as an integration point involved in a wide variety of cellular processes such as proliferation differentiation transcription regulation and development including regulation of regional specific apoptosis during early brain development

MAPK9 ge70 SDS-PAGE SRP5042-10UG

c-Jun human Substrate for SAPK1JNK2 JUN 40-50 SDS-PAGE C5859-100UG

8 p300 human EP300 and CREBBP are highly related transcriptional coactivators mediating cAMP gene regulation EP300 is known to acetylate many transcription factors including p53 E2F TFIIE and TFIIF

EP300 ge70 SDS-PAGE SRP2079-4UG

p53 human p53 gene is highly conserved and expressed in normal tissues It is the most commonly mutated gene in human cancer and more then 500 gene mutations have been described in various types of malignancies hematologic as well as solid tumors Intact p53 function is essential for the maintenance of the non-tumorogenic phenotype of cells Thus p53 plays a vital role in suppressing the development of cancer

TP53 ge90 SDS-PAGE P6249-50UG



p53 Mutant human p53 is a tumor suppressor gene expressed in a wide variety of tissue types and is involved in regulating cell growth replication and apoptosis Mutation involving p53 is found in a wide variety of malignant tumors including breast ovarian bladder colon lung and melanoma

TP53 ge90 HPLCge90 SDS-PAGE

SRP4832-5UG

PDK1 Active human PDK1 plays a regulatory role in glucose and carbohydrate metabolism It functions through the PI3K signaling cascade upstream of AKT1 as well as in other pathways involving proliferation survival and cell migration

PDPK1 ge75 SDS-PAGE P7498-5UG

PDK1 active His tagged human

PDK1 plays a key regulatory role in the homeostasis of carbohydrate fuels It activates protein kinase B (PKB) which in turn inactivates GSK3 and may potentiate the effects of IGF1

PDPK1 ge70 SDS-PAGE K3393-10UG

RACK1 human RACK1 is an intracellular receptor protein that binds activated members of the protein kinase C family

GNB2L1 gt90 SDS-PAGE R4780-50UG

8 TATA box binding protein GST tagged human

TBP is the core protein of the transcription factor IID complex the multiprotein DNA-binding factor that coordinates activities necessary for initiation of transcription by RNA polymerase II

TBP ge70 SDS-PAGE SRP2106-10UG

8 TBP (TATA box binding protein) human



To view additional products for Huntingtons Disease Research visit sigmacomhunt

Antibody catalog numbers beginning with HPA are Prestige Antibodiesreg powered by Atlas Antibodies

Proteins amp Peptides for Huntingtonprimes Research continued

Order sigmacomorder Technical service sigmacomtechinfo sigmacomlifescience 15biomolecules

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Visit sigmacomneuropeptides to browse β-amyloids neurotransmitters vasoactives and more

copy2012 Sigma-Aldrich Co LLC All rights reserved SIGMA and SIGMA-ALDRICH are trademarks of Sigma-Aldrich Co LLCregistered in the US and other countries Where bio begins is a trademark of Sigma-Aldrich Co LLC

16

Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers disease affecting more than 6 million people worldwide PD is a slowly progressing motor system neurodegeneration characterized by akinesia rigidity and resting tremor Neuropathologically PD is characterized by loss of dopaminergic cell bodies in the substantia nigra resulting in a reduced supply of dopamine to the basal ganglia The high metabolic rate of the substantia nigra combined with high content of oxidizable species and iron high levels of reactive oxygen species (ROS) and low level of antioxidants all serve to initiate and propagate apoptosis of the dopaminergic neurons

Mutations in the α-synuclein gene (SNCA) occur in familial cases of Parkinsons disease pointing to a role for this gene in PD α-Synuclein can form protein aggregates with additional cytoskeletal proteins including synaptophysin (SYP) and Tau (MAPT) which are believed to lead to the pathogenesis of Lewy body formation

Synphilin (SNCAIP) interacts with α-synuclein in neuronal tissue and is thought to play a role in the formation of cytoplasmic inclusions and neurodegeneration A mutation in this gene has been associated with Parkinsons disease

Mutations in the LRRK2 (PARK8) gene are found in about 5-6 percent of all familial cases as well as 2 percent of cases with no known cause Interestingly this mutation can cause early-onset Parkinsons in families from diverse ethnic backgrounds in a form that is

identical in clinical symptoms to late-onset Parkinsons LRRK2 encodes a protein that is part of a larger multidomain protein with characteristic GTPase and kinase domains LRRK2s substrates its binding partners and its regulators have yet to be confirmed or clarified and consequently its role in normal physiological functions in the cell and in disease are still largely unknown

Loss of function mutations in the Parkin (PARK2) PINK1 (PARK6) and PARK7 (DJ-1) genes resulting in functionally inactive proteins underlie common forms of autosomal-recessive PD Patients with loss-

of-function Parkin mutations account for an estimated 40-50 percent of all familial early-onset cases of PD whereas mutations in PINK1 and PARK7 are less common Several studies have demonstrated that products of all three recessive genes preserve mitochondrial functions protect against reactive oxygen species or play a role in protein degradation pathways Normally Parkin tags proteins with ubiquitin for degradation via the proteasome Mutations in the Parkin gene lead to a loss of this activity DJ-1 is a molecular chaperone involved in protein folding as well as in

Parkinsons Disease Antibodies Proteins and Peptides

Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation

Death ofDopaminergic

Neurons

Parkinsonrsquos Disease

Accumulation of PAELR in the ER

Inhibition ofDopamine Release

CytoplasmicAccumulation of

Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P

Production ofReactive Oxygen

Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup

UbiquitinationPathway

SEPT5Ub

Accumulation of O-glycosylated

Synuclein-αAccumulation of

SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP

LigandepenNucleRecep

ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro

oTranslatiorRegulato

Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub

Parkinsons Signaling For this and related interactive pathways see sigmacompdsig


other functions It is found in the cytosol the mitochondrial matrix and intermembrane space It regulates redox-dependent signaling pathways and acts as a regulator of antioxidant gene expression

UCHL1 (PARK5) is a member of the ubiquitin-C-terminal hydrolases Expression of UCHL1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors A point mutation I93M in this protein is implicated as the cause of PD Furthermore a polymorphism S18Y in this gene has been found to be associated with a reduced risk for Parkinsons disease UCH-L1 is also associated with the Alzheimers disease

The ATP13A2 (PARK9) gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS) also referred to as Parkinson disease 9 and in juvenile forms of PD

Additional genes including GIGYF2 (PARK11) HTRA2 (OMI PARK13) PLA2G6 (PARK14) FBXO7 (PARK15) STUB1 (CHIP) and RNF19A (Dorfin) are thought to be implicated in PD

With its complex etiology and impact on millions Parkinsons Disease continues to be the subject of intensive research effort

References1 Pawlyk AC et al Novel monoclonal antibodies

demonstrate biochemical variation of brain parkin with age J Biol Chem 2003 278 48120-48128

2 Kitada T et al Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism Nature 1998 392 605-608



5 Kurihara LJ et al Loss of Uch-L1 and Uch-L3 leads to neurodegeneration posterior paralysis and dysphagia Hum Mol Genet 2001 10 1963-1970

6 Leroy E et al The ubiquitin pathway in Parkinsons disease Nature 1998 395 451-452

7 Levecque C et al No genetic association of the ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism with familial Parkinsons disease J Neural Transm 2001 108 979-984

8 Liu Y et al The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinsons disease susceptibility Cell 2002 111 209-218

9 Lee G et al Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival J Neurochem 2002 83 346-352

10 Nagano Y et al Siah-1 facilitates ubiquitination and degradation of synphilin-1 J Biol Chem 2003 278 51504-51514

11 Liani E Ubiquitylation of synphilin-1 and alpha-synu-clein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinsons disease Proc Natl Acad Sci USA 2004 101 5500-5505

12 Arai R et al Differential subcellular location of mitochondria in rat serotonergic neurons depends on the presence and the absence of monoamine oxidase type B Neurosci 2002 114 825-835

13 Fernandez HH and Chen JJ Monamine oxidase inhibitors current and emerging agents for Parkinson disease Clin Neuropharmacol 2007 30 150-168

14 Hishikawa N et al Dorfin localizes to the ubiquitylated inclusions in Parkinsons disease dementia with Lewy bodies multiple system atrophy and amyotrophic lateral sclerosis Am J Pathol 2003 163 609-619

15 Ito T et al Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1 J Biol Chem 2003 278 29106-29114

16 Paisan-Ruiz C et al Cloning of the gene containing mutations that cause PARK8-linked Parkinsons disease Neuron 2004 44 595-600

17 West AB et al Parkinsons disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity Proc Natl Acad Sci USA 2005 102 16842-16847

18 Cookson MR et al The roles of kinases in familial Parkinsons disease J Neurosci 2007 27 11865-11868

19 Valente EM et al Hereditary early-onset Parkinsons disease caused by mutations in PINK1 Science 2004 304 1158-1160

20 Beilina A et al Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability Proc Natl Acad Sci USA 2005 102 5703-5708

21 Park J et al Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin Nature 2006 441 1157-1161

22 Torres GE et al Plasma membrane monoamine transporters structure regulation and function Nature Rev Neurosci 2003 4 13-25

23 Ciliax BJ et al Immunocytochemical localization of the dopamine transporter in human brain J Comp Neurol 1999 409 38-56

24 Gandhi S et al PINK1 protein in normal human brain and Parkinsons disease Brain 2006 129 1720-1731

25 Ramirez A et al Hereditary parkinsonism with dementia is caused by mutations in ATP13A2 encoding a lysosomal type 5 P-type ATPase Nature Genet 2006 38 1184-1191

26 Wei J et al Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies J Biol Chem 2007 282 28904-28914

27 Ning YP et al PARK9-linked parkinsonism in eastern Asia mutation detection in ATP13A2 and clinical phenotype Neurol 2008 70 1491-1493

28 Hod Y Differential control of apoptosis by DJ-1 in prostate benign and cancer cells J Cell Biochem 2004 92 1221-1233

29 Bonifati V et al Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism Science 2003 299 256-259

30 Faccio L et al Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia J Biol Chem 2000 275 2581-2588

31 Strauss KM et al Loss of function mutations in the gene encoding OmiHtrA2 in Parkinsons disease Hum Mol Genet 2005 14 2099-2111

32 Park HJ et al Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease Implications for the physiological function of HtrA2 in the mitochondria J Biol Chem 2006 281 34277-34287

33 Morgan NV et al PLA2G6 encoding a phospholipase A2 is mutated in neurodegenerative disorders with high brain iron Nat Genet 2006 38 752-754

34 Gregory A et al Neurodegeneration associated with genetic defects in phospholipase A(2) Neurol 2008 71 1402-1409

35 Schaeffer EL and Gattaz WF Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease participation of the phospholipase A2 enzyme Psychopharmacol 2008 198 1-27

36 Petrucelli L et al CHIP and Hsp70 regulate tau ubiquitination degradation and aggregation Hum Mol Genet 2004 13 703-714

37 Shin Y et al The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways J Biol Chem 2005 280 23727-23734

38 Miller VM et al CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo J Neurosci 2005 25 9152-9161

18

Antibodies for Parkinsons ResearchProduct Name Host Clone No Gene Symbol Species Reactivity Application Array Antibody Cat NoAnti-ATP13A2 (C-terminal region) rabbit - ATP13A2 human human

mouseWB - A3361-25UL

A3361-200UL

Anti-Caspase 3 Active rabbit - Casp3 mouseCASP3 human

Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL

Anti-Caspase 9 rabbit - CASP9 humanCasp9 rat

humanrat

ARRIHC (p)

IPWB

- C7729-2ML

Anti-CHIP (N-terminal) rabbit - Stub1 mouseK08D1011 ratSTUB1 human

humanmouse

rat

WB - C9118-25ULC9118-200UL

Anti-Cytochrome c sheep - CYCS humanCycs rat

caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL

Monoclonal Anti-DOPA Decarboxylase (DDC)

mouse DDC-109 DDC humanDdc rat

bovinecanine

guinea pighumanmonkey

rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML

Anti-Dorfin (N-terminal) rabbit - Rnf19a mouseRNF19A human

humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL

Anti-HtrA2 rabbit - Htra2 ratHTRA2 human

humanrat

WB H7290-25ULH7290-200UL

Monoclonal Anti-LRRK2 mouse PROK57 LRRK2 humanLrrk2 mouse

humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL

Anti-LRRK2 (C-terminal region) rabbit - Lrrk2 mouseLRRK2 human

Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL



Monoclonal Anti-p38 MAP Kinase Activated (Diphosphorylated p38)

mouse P38-TY Mapk14 ratMapk14 mouseMAPK14 human

humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML

Anti-PARK7 rabbit - PARK7 human human IF (i)IHC (p)

PAWB

- HPA004190-100UL

Monoclonal Anti-Parkin mouse PRK8 Park2 ratPARK2 humanPark2 mouse

hamsterhumanmouse

rat

ARRWB

P6248-200UL

Anti-Phospholipase A2 (iPLA2) rabbit - pla2g6 ratpla2g6 mouse

PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL

Anti-PINK1 rabbit - Pink1 ratPink1 mousePINK1 human

humanmouse (predicted)

rat (predicted)

WB P0076-25ULP0076-200UL

Anti-SEPT5 (1-14) rabbit - SEPT5 human human IF (i)WB

- SAB1100586-200UL


- SAB1100587-200UL

Anti-Synphilin-1 rabbit - Sncaip ratSncaip mouseSNCAIP human

human WB S5946-200UL


Product Name Host Clone No Gene Symbol Species Reactivity Application Array Antibody Cat NoAnti-Synphilin-1 (C-terminal) rabbit - SNCAIP human

Sncaip ratSncaip mouse


Anti-α-Synuclein rabbit - Snca ratSNCA human

humanrat

ARRIHC (p)

WB

S3062-2ML

Anti-Ubiquitin C-terminal Hydrolase L1 (RA-15)

rabbit - Uchl1 mouseUchl1 rat

UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL

Proteins amp Peptides for Parkinsonprimes Research Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No Caspase 3 human Member of the CED-3 subfamily of caspases and responsible for the cleavage

of many key proteins such as the nuclear enzyme poly(ADP-ribose) polymerase (PARP) the inhibitor of caspase-activated deoxyribonuclease (ICAD) and gelsolin a protein involved in apoptosis regulation Human recombinant C-terminal histidine tagged caspase 3 is a fully active protein consisting of 17 kDa and 135 kDa subunits the 135 kDa subunit contains the histidine tag

CASP3 ge90 SDS-PAGE C1224-10UG

Caspase 9 human Activation of caspase-9 (CASP9) through apoptotic stimuli initiates the caspase cascade Caspases have been implicated in many disorders including cancer inflammatory disease neurodegenerative diseases stroke and myocardial infarction


Cytochrome c from human heart

Cytochrome c is a small heme protein that is a mobile electron carrier in the mitochondrial electron transport chain It is also an initiator of apoptosis

CYCSL1CYCS


JNK1 active GST tagged from mouse

JNK1 is a member of the MAP kinase family that plays a role in the induction of apoptosis Disruption of MAP kinase signaling functionality is associated with disease states including inflammation cancer and neurodegenerative disease

Mapk8 ge70 SDS-PAGE J2455-10UG

p38α active GST tagged human

MAPK14 is a member of the p38 MAPK family members of which are activated by various environmental stresses and proinflammatory cytokines Suggested roles of this kinase include involvement in stress related transcription cell cycle regulation and genotoxic stress response

MAPK14 ge70 SDS-PAGE A4861-10UG

p38β active GST tagged human

p38β is a member of the p38 MAP kinase family and is activated by both proinflammatory cytokines and environmental stress The p38β is activated through its phosphorylation by MAP kinase kinases (MKKs) preferably by MKK6 Transcription factor ATF2CREB2 has been shown to be a substrate of this kinaseAlternatively spliced transcript variants encoding the same protein have been observed

MAPK11 ge70 SDS-PAGE B4437-10UG

Immunofluorescence of HUVEC cells using MAPK11 (306-320) (RB) Cat No M1322 Yale HTCB IF procedure used

Anti-PARK7 Cat No HPA004190 Immunofluorescent staining of human cell line U-2 OS

20

Product Name BiochemicalPhysiological Actions Gene Symbol Purity Cat No p38γ active

GST tagged humanp38γ is a member of the p38 MAPK family which is activated in response to stress p38γ gene was mapped to 22q133 and functions as a signal transducer during differentiation of myoblasts to myotubes Enforced localization of p38γ in the nucleus or cytoplasm markedly attenuates the ability of the kinase to induce cell cycle arrest in fibroblasts p38γ increases basal glucose uptake and decreases DNP- and contraction-stimulated glucose uptake partially by affecting levels of glucose transporter expression in skeletal muscle

MAPK12 ge70 SDS-PAGE G8546-10UG

p38δ active GST tagged human

p38δ (SAPK4) is a member of the p38 MAPK family and is activated by chemical and environmental stresses as well as by proinflammatory cytokines p38δ has a TGY dual phosphorylation motif and is activated in response to cellular stresses and proinflammatory cytokines MAP kinase kinases 3 and 6 can phosphorylate and activate this kinase Transcription factor ATF2 and microtubule dynamics regulator stathmin have been shown to be the substrates of this kinase

MAPK13 ge70 SDS-PAGE D7444-10UG

Parkin N-Terminal Peptide Used as marker for degradation of parkin PARK2 ge60 HPLC P2615-1MG

α-Synuclein human 140-amino acid protein (apparent molecular mass 19-20 kDa) that induces polymerization of tubulin into microtubules and functions in the modulation of dopamine

SNCA ge90 SDS-PAGE S7820-500UG

α-Synuclein A30P human A point mutation in the α-synuclein gene Ala30-Pro (A30P) linked to familial Parkinsons disease


α-Synuclein A53T human A point mutation in the α-synuclein gene A53T (Ala53-Thr) is linked to familial Parkinsons disease


α-Synuclein E46K human Deposition of α-synuclein as fibrillary tangles is a hallmark of certain neurodegenerative diseases including Parkinsons Among the familial mutations of α-synuclein E46K has the greatest potential to aggregate


8 UCHL1 His tagged human UCHL1 has ligase and hydrolase activities which play roles in proteasomal protein degradation a process critical for neuronal health Mutations in UCHL1 may be associated with Parkinsons disease and UCHL1 reverses the inhibition of CREB phosphorylation induced by Amyloid-β

UCHL1 ge70 SDS-PAGE SRP5149-50UG

To view additional products for Parkinsons Disease Research visit sigmacompark

Proteins amp Peptides for Parkinsonprimes Research continued


Antibody microarrays are used for profiling complex protein samples and for assessing differential protein expression The Panorama Ab Microarray kits consisting of a series of arrays that cover various biological pathways such as Cell Signaling Gene Regulation and MAPKPKC pathways have already proven to be useful tools for such applications A new antibody array consisting of 224 neurobiology related antibodies has been developed Refer to Figure 1 for antibody distribution

Using this array we compared brain tissue of newborn and adult rats in order to study protein expression during rat brain development We identified several proteins that changed with age The outline of the experimental procedure is highlighted in Figure 2

Differential protein expression in rat models using the Panoramareg Neurobiology Array

Panoramareg Neurobiology Array

Developmental 40

BiopolarDepression 1

Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2

Figure 1 ndash Distribution of neurospecific antibodies comprising the Panorama Neuorobiology Array

Step 2Label samples with Cy3Cy5

and mix

Step 3Incubate on the array

Step 4Scan the array

Sample BSample A

Step1Extract proteins

Figure 2 ndash Neurobiology Antibody Array Procedure

For a listing of antibodies on the array scan the QR code or visit sigmacomnbaa5

22

Expression of proteins were prepared from rat newborn (4 days) and adult (2 month) brains using ExtractionLabeling Buffer (as supplied in Panoramareg Neurobiology kit) and labeled with Cy3trade Equal amounts of labeled extracts (20 μgml) were incubated on the Neurobiology slides Proteins on left (indicated in green) demonstrate decline in development Proteins on right (indicated in

red ie Synaptopodin Ubiquitin C-terminal Hydolase L1 and alphabeta SNAP) are associated with increase with age Figure 3

Array results were confirmed by immunoblotting Equal amounts of protein extract (20 μg per lane) from rat adult (A) or newborn (N) brains were separated by SDS-PAGE and blotted onto nitrocellulose

membrane The proteins were probed with the monoclonal or polyclonal antibodies corresponding to the array and visualized using chemiluminescence

Further studies using the Panorama Neurobiology array have been performed identifying several additional proteins that changed with age For example PINK1 was shown to be elevated in adult versus newborn brains Further evaluation of the new Panorama Antibody Neurobiology Array was performed using brain tissue from the knockout rat model PARK2 -- The array has demonstrated that indeed this gene expression is being ablated in the knockout rats versus wild type siblings a result validated by immunoblotting (data not shown)

In conclusion the new Panorama Neurobiology array has shown to be a promising and useful tool for high-throughput screening (HTS) of protein level changes in neuronal development and neurodegenerative disease

Newborn Adult

AL S2CL (N-terminal region)

AL S2CL (N-terminal)

TAU

Synaptopodin

Ubiquitin C-terminalHydrolase L1

αβ SNAPHigh level

Low level

A N

A N

A N

A N

Figure 3 ndash Differential Expression between Newborn and Adult Rats

biomolecules

BioguaranteeSigmareg Life Science offers a collection of more than 50000 antibodies all 100 BioguaranteedFind the antibody you needsigmacomantibodyexplorer

copy2012 Sigma-Aldrich Co LLC All rights reserved SIGMA and SIGMA-ALDRICH are trademarks of Sigma-Aldrich Co LLC registered in the US and other countries Where bio begins is a trademark of Sigma-Aldrich Co LLC

Experimental results must be submitted via the Antibody Bioguarantee Form within 12 months of the date of purchase All required fi elds of the Antibody Bioguarantee Form must be completed Refunds and replacements contingent to claim review by technical service team Credit covers the cost of antibody Product replacements depend on product availability


copy2012 Sigma-Aldrich Co LLC All rights reserved SIGMA and SIGMA-ALDRICH are trademarks of Sigma-Aldrich Co LLC registered in the US and other countries SAGE and Where bio begins are trademarks of Sigma-Aldrich Co LLC

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Biofilescontents

Introduction 3

Alzheimers Disease Antibodies Proteins Peptides and Assays 4

Huntingtons Disease Antibodies Proteins and Peptides 9

Parkinsons Disease Antibodies Proteins and Peptides 16

Differential protein expression in rat models using the Panoramareg Neurobiology Array 21

BiofilesonlineYour gateway to Biochemicals and Reagents

for Life Science Research

Biofiles Online allows you to

bullEasily navigate the content of the current Biofiles issue

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Register today for upcoming issues and eBiofiles announcements at

sigmacombiofiles

Highlights from this issue This issue of Biofiles highlights current

research in the areas of Alzheimerrsquos Parkinsonrsquos and Huntingtonrsquos disease

as representative of major efforts to delineate key events in the development

of neurodegenerative diseases Neurodegenerative diseases affect the central nervous system causing

progressive nervous system dysfunction These debilitating and incurable conditions are characterized by loss of neuronal cell function

and are often associated with atrophy of the affected nervous system structures Products featured in this issue include antibodies proteins peptides and assays which represent a broader set of tools offered to

support basic research in neurodegenerative disease

Coming next issue The next issue of Biofiles highlights Epigenetics the study of stable but

potentially reversible alterations in gene expression that occur

without permanent changes in DNA sequence The significance of epigenetic

changes in the development of cancer autism and other diseases is being increasingly recognized Given this developing mechanistic

understanding the field is attracting investigators interested in diverse aspects of chromatin and chromosome biology

Technical contentCarolyn L CrankshawProduct Specialistcarolyncrankshawsialcom

Dr Eliezer KopfManager Manufacturing eliezerkopfsialcom














4







Extracellular Space

Cytoplasm

Amyloid-β


Lipidperoxidation

Membranedamage

Neuronal death




Membranedamage

Hyperphosphorylated


P

TAU

p35

p25

CDK5

ERK12

CK12

p38 MAPK

PKA

PKCε

MARK

neCa2+

γ-secretase

β-secretase

AKTCDK5

GSK-3β

Calpain

X

γ-secretase

β-secretase

TAU



Enzyme


Group orComplex

Ion Channel

Kinase


OxidizedProtein


microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

iT

xicant

r c

microRN

a

a

r ct a

h

tor Peptida

Phosph

Kinase

ndenleaep

Phosh

LigadepeNucRece

el

ipio

io

Transme



T


lated

t

o

Mutated

Transpo

Other

P

O





























IHC (p)WB

A3981-25ULA3981-200UL


- A5213-2ML


rat

ELISA (i)WB

- SAB2500076-100UG



WB

A8599-100UL



- B7935-200UL



Capn3 rat

humanmouse

rat

WB - C0728-1MG



humanrat

ARRWB

- G7914-2ML


Lrp1 rat

humanmouse

rat

IF (i)WBWB

L2170-25ULL2170-200UL


human IPWB

L2045-25ULL2045-200UL


6





Xenopusbovine

hamsterhumanmouse

ratyeast

ELISA (i)ICC

IHC (p)IP

WB

- M8159-2ML






Xenopusbovine

hamsterhumanmouse

ratyeast

ARRELISA (i)

ICCIHC (p)

IPWB

M9692-200UL


rat

ARRIF (i)

IPWB

N1660-2ML


humanrat

ARRWB

- P9489-2ML


human ARRWB

P5622-200UL


Akt1 mouse

mouserat

ARRWB

- P4112-2ML


PSEN1 human

Xenopushumanmouse

rat

ARRIHC (p)

WB

P7854-2ML



WB T6402-2MLT6402-1ML


ARRIHC (p)

WB

T5530-2MLT5530-5ML


Tmed10 mouse

humanmouse

rat

WB T3827-25ULT3827-200UL



bovinefeline

humanmouse

pigrabbit

ratsheep

IF (i)IHC (p)

IPWB

- V2258-2MLV2258-5ML



























A3234-100UG



CDK5CDK5R1












8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238















4







Extracellular Space

Cytoplasm

Amyloid-β


Lipidperoxidation

Membranedamage

Neuronal death




Membranedamage

Hyperphosphorylated


P

TAU

p35

p25

CDK5

ERK12

CK12

p38 MAPK

PKA

PKCε

MARK

neCa2+

γ-secretase

β-secretase

AKTCDK5

GSK-3β

Calpain

X

γ-secretase

β-secretase

TAU



Enzyme


Group orComplex

Ion Channel

Kinase


OxidizedProtein


microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

iT

xicant

r c

microRN

a

a

r ct a

h

tor Peptida

Phosph

Kinase

ndenleaep

Phosh

LigadepeNucRece

el

ipio

io

Transme



T


lated

t

o

Mutated

Transpo

Other

P

O





























IHC (p)WB

A3981-25ULA3981-200UL


- A5213-2ML


rat

ELISA (i)WB

- SAB2500076-100UG



WB

A8599-100UL



- B7935-200UL



Capn3 rat

humanmouse

rat

WB - C0728-1MG



humanrat

ARRWB

- G7914-2ML


Lrp1 rat

humanmouse

rat

IF (i)WBWB

L2170-25ULL2170-200UL


human IPWB

L2045-25ULL2045-200UL


6





Xenopusbovine

hamsterhumanmouse

ratyeast

ELISA (i)ICC

IHC (p)IP

WB

- M8159-2ML






Xenopusbovine

hamsterhumanmouse

ratyeast

ARRELISA (i)

ICCIHC (p)

IPWB

M9692-200UL


rat

ARRIF (i)

IPWB

N1660-2ML


humanrat

ARRWB

- P9489-2ML


human ARRWB

P5622-200UL


Akt1 mouse

mouserat

ARRWB

- P4112-2ML


PSEN1 human

Xenopushumanmouse

rat

ARRIHC (p)

WB

P7854-2ML



WB T6402-2MLT6402-1ML


ARRIHC (p)

WB

T5530-2MLT5530-5ML


Tmed10 mouse

humanmouse

rat

WB T3827-25ULT3827-200UL



bovinefeline

humanmouse

pigrabbit

ratsheep

IF (i)IHC (p)

IPWB

- V2258-2MLV2258-5ML



























A3234-100UG



CDK5CDK5R1












8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238





























IHC (p)WB

A3981-25ULA3981-200UL


- A5213-2ML


rat

ELISA (i)WB

- SAB2500076-100UG



WB

A8599-100UL



- B7935-200UL



Capn3 rat

humanmouse

rat

WB - C0728-1MG



humanrat

ARRWB

- G7914-2ML


Lrp1 rat

humanmouse

rat

IF (i)WBWB

L2170-25ULL2170-200UL


human IPWB

L2045-25ULL2045-200UL


6





Xenopusbovine

hamsterhumanmouse

ratyeast

ELISA (i)ICC

IHC (p)IP

WB

- M8159-2ML






Xenopusbovine

hamsterhumanmouse

ratyeast

ARRELISA (i)

ICCIHC (p)

IPWB

M9692-200UL


rat

ARRIF (i)

IPWB

N1660-2ML


humanrat

ARRWB

- P9489-2ML


human ARRWB

P5622-200UL


Akt1 mouse

mouserat

ARRWB

- P4112-2ML


PSEN1 human

Xenopushumanmouse

rat

ARRIHC (p)

WB

P7854-2ML



WB T6402-2MLT6402-1ML


ARRIHC (p)

WB

T5530-2MLT5530-5ML


Tmed10 mouse

humanmouse

rat

WB T3827-25ULT3827-200UL



bovinefeline

humanmouse

pigrabbit

ratsheep

IF (i)IHC (p)

IPWB

- V2258-2MLV2258-5ML



























A3234-100UG



CDK5CDK5R1












8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


6





Xenopusbovine

hamsterhumanmouse

ratyeast

ELISA (i)ICC

IHC (p)IP

WB

- M8159-2ML






Xenopusbovine

hamsterhumanmouse

ratyeast

ARRELISA (i)

ICCIHC (p)

IPWB

M9692-200UL


rat

ARRIF (i)

IPWB

N1660-2ML


humanrat

ARRWB

- P9489-2ML


human ARRWB

P5622-200UL


Akt1 mouse

mouserat

ARRWB

- P4112-2ML


PSEN1 human

Xenopushumanmouse

rat

ARRIHC (p)

WB

P7854-2ML



WB T6402-2MLT6402-1ML


ARRIHC (p)

WB

T5530-2MLT5530-5ML


Tmed10 mouse

humanmouse

rat

WB T3827-25ULT3827-200UL



bovinefeline

humanmouse

pigrabbit

ratsheep

IF (i)IHC (p)

IPWB

- V2258-2MLV2258-5ML



























A3234-100UG



CDK5CDK5R1












8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




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A3234-100UG



CDK5CDK5R1












8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


8



























CS1060-1KT



CS0010-1KT


































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238

































Huntingtons Disease

10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




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DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



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SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



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ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


10


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub


Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238



Gene Transcription


Caspase 8Caspase 8

Caspase 37

Caspase 12

Calpain

Ca2+

Ca2+


GRM15

Caspas

Ca2+

Ca2+



Neurodegeneration

HD

Bax

HD


Inclusion

Cytochrome c

CaCC 2++

Ca

Baax

HD

Gβ

Gγ

se

HIP 1

HD

se 12

HIP

HD

HIPPI

Bcl-xI

HIP 11HIP 1

Bcl-xIB l I

Altered in HD




HDFragment

HD

HD

HD

HD

HD

HIPPIHIPPI

HD

1

Apaf 1

CCaspas

ochrome c

CCaspas

Apaf 1

Calpain

CDK5

p35

SGK AKT

PDK1

PIP3IP3

GαqPLCβ

PSD-95

PKC DAG

PI3K

IGF1R

IGF-1

PIP2PIP2

HAP1

Caspase

mTOR

Ca2+

PIP33PIP22

HDFragment

HDCse

HD Fragment

Neuro

ragment

P

HD

p35

HD P

HD

HD

HD

Ca2+

PIP2

SGK

HAP1


DAG

D

HD

HD

HDFragment

DNAJC5

HDFragment

HD

HD

DNAJC5DSTX1A

HD

Ca2+

Glutamate

Ca2+

GR

GlutamateCa2+

a2+ Channel

PHD

NCOR

TGM2CBP

HD Fragment

CB

NeuI t

SH3GL3

uclearsion

nuus

IntranInclu

p53

sionusInclu

SP1

p53

SIN3A

SP1

CA150BP

TGBP

GMGGMM2M2

ntennten SIN3A

CA150TBP

NCOOR

SH3GGL33


TAFII130

CBP HDFragment


TFIIDCBPFra

HDntagmen

TFIID

TBP

Gene Transcription


HIP 1HIP 1

HIPPI

HIP 1

HD

HIP 1

HDHDDDHD

CREB

CRE

CREB

CRE

Autophagy

Polymerase II

Cytochrome c

Mitochondria

SR

mTOR

Arfaptin 2ArfaptinP

IP33

HDMisfolded

HP14

Endocytosis

HD

HP14HP14HP14

HD

Impaired Exocytosis

SNARE RPH3A


SynapticVesicle

1


n 2P

HD

E

d in HD

RPH3A

Reduced in HDSTX1A




EGF

HD

HD

RASGAP

hRas

HD

HD

HDJNK1

NGF

PI3K

hRas

ERK 12AKT1

HD

EGF


HD

HD

hRas

HD

SOS

GBR2

SOS

GBR2 SHC HD hRas

GRB2

SOSSSHC

RASGAP

HD AA

HD HAP1

HD

HDMLK2

MLK2

MLK2

MLK2

NeuroD

MKK 47

JNK2

JNK2

p53C-Jun

P1

Gene Transcription


SurvivalApoptosis

HD

MLK2

MLK2

HD HAP

HD

MLK2

NeuroD

p53p53C-Junun

P

HDHD

P

Gene Transcription

BDNF

Cell Death

REST

RESTREST

HD

RESTR

HD

R

HD

RCOR HDAC

SIN3A

RRCOR HDAC

REST

REST

REST

REST

REST HD

Polymerase II

BDNF

NRSE


Cell Death

Proteasome

Protein Degradation

dHD

Misfolded

Ub

Ub

Hsp70

Hsp40

HD

HDMisfolded

UBE2S

SH3GL3

Hsp40

HDFragment

HDMisfolded

HIP1

DCTN1

HIP1

TN1DCT

SNCADNM

GLS

SDH

Hsp40Hsp40HH

ATP5

DCTN1

Hsp40

HAP1

DYNC1I2

1DCTN1HAP1

DYNC1I2DYNC1I2

HD

HAP1HAP1

HD


NeurotoxicityDeath



HDHD

HIP1 CLTC

Hsp40

AP2

HHIP1 CLTC

AP2

HD

Clathrin-coated

Vesicles

Clathrin-coated

Vesicles

Clathrin-t d

BDNF

Vesiccles

BDNF

11

0Hsp40

siclesVes

TGM2


TN1DCT

SNCASDH

Ub

D

rinuclearclusions

LSGLSUb

SH3GGL3HHHD

Hsp70CTSD

DHD

Dment

DNMDNM

t

MM S

DHHgFragHDm

DD

HHHD

Hsp70CTSD

Microtubules

Cytoplasm

Extracellular Space

Nucleus

ITPR1

HD

P PP P

P P

Caspase 9

HD

Appaf

Casppase 9p

CPLX2SNARE

Reduced

CPPLX2



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

scTrans

oa

micro

d

pp

oac

id

p

r ctor

Pepti

Phos

Kina

gaepeucece

Ph

LigdeNuRe

el

p

cca

aa

scTranscca

lTranslRegulaRegul

TranscRegulTrans

t

Mutat

t

Transp

Othe


Ub

12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


12


WB- SAB1402127-100UG


WB

- SAB1403694-100UG


- HPA030320-100UL


PA

- HPA003128-100UL



Grin1 mouse

humanmouse

rat

WB - G8913-2ML



PAWB

- HPA013606-100UL



rat

WB H7414-25ULH7414-200UL



humanmouse

ARRELISA (i)

IPWB

- H6287-200UL



Hdac2 rat


rat

ARRELISA (i)

IHCIP

WB

- H2663-200UL



humanmouse

rat

ICCIP

WB

- H0163-200UL



Hdac5 rat

humanmouse

rat

ARRELISA (i)

ICCIP

WB

- H4538-200UL




Neurod1 mouse

humanmouse

rat

WB - N3663-25ULN3663-200UL


WB

P1874-200UL


PA

- HPA006079-100UL


human ARRIP

WB

- S6695-200UL



humanyeast

IPWB

- T1827-25ULT1827-200UL









SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238










SRP3014-10UG

























SRP4121-20UG

14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


14




I3769-50UG

























SRP4832-5UG























16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238








16









Parkinsons Disease

SYPH1

p38MAPKJNK1

Synuclein-α

Cytoplasm

PAELR

UCHL1

PARK7 PARK3

PARK4

Lewy BodyFormation


Neurons





Dopamine

SYPH1 PAELR

PARK4

PARK3PARK7

UbSynuclein-αα

Ub Ub

Parkin Ub

P


Species

Cytochrome c

Caspase 9

Caspase 3

O-glycosylgroup


SEPT5Ub



SYPH1



Enzyme


Group orComplex

Ion Channel

Kinase



microRNA

Peptidase

Phosphatase




Transporter

Other

Key


Direct Interaction


A B Bindings Only

A B Inhibits


A B Leads To

A B Translocates To

A B Reaction

A B

A B


Disruption

Mutated Gene

A B Acts On

cal ccrrorn

nhh

microRNA

e

tt

rrrnnn

nnnhhhhh

se

at

rrt

e orFFactor

Peptidas

Phospha

e

phi

d-nd

earpto

Prote

Kinase

PhospP


ex

annel

Receptor

t

tr

or

m

m

teet

p le

e

ee

ex Transmem

eeinedtoor

orex

ptpro


Transmem

eein

po

T l ti

TranscripRegulato

eeee

ex Transmem

-dror Mutated

-dro

-dentr

Transport

Other

M d


Ub















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238















































18



A3361-200UL


Casp3 rat


pigrat

ARRIF (i)WB

- C8487-200UL


humanrat

ARRIHC (p)

IPWB

- C7729-2ML


humanmouse

rat

WB - C9118-25ULC9118-200UL


caninehumanrabbit

rat

IF (i)IHC (p)

WB

- C9616-200UL



bovinecanine


rabbitrat

sheep

ARRELISA (i)

ICCIP

WB

D0180-2MLD0180-5ML


humanmouse

rat (predicted)

WB D0319-25ULD0319-200UL


humanrat

WB H7290-25ULH7290-200UL


humanmouse

ELISA (i)ICCWB

L3044-25ULL3044-200UL


Lrrk2 rat

humanmouse

rat

WB L9918-25ULL9918-200UL





humanmouse

rat

ARRELISA (i)

ICCWB

- M8177-2ML


PAWB

- HPA004190-100UL


hamsterhumanmouse

rat

ARRWB

P6248-200UL


PLA2G6 human

humanmouse

rat

WB - SAB4200129-25ULSAB4200129-200UL



rat (predicted)

WB P0076-25ULP0076-200UL


- SAB1100586-200UL


- SAB1100587-200UL








humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238







humanrat

ARRIHC (p)

WB

S3062-2ML



UCHL1 human

humanmouse

rat

ARRWBWB

U5258-200UL








CYCSL1CYCS













20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


20

























Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238







Developmental 40


Parkinsons 13

Schizophrenia 9

Alzheimers 21

ALS 8Huntingtons 6

MS 2



and mix



Sample BSample A




22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


22







Newborn Adult



TAU

Synaptopodin


αβ SNAPHigh level

Low level

A N

A N

A N

A N


biomolecules






bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238




bioengineering

Biosynaptic









NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238




NYD77157-510122

1121



St Louis MO 63103 (314) 771-5765

sigma-aldrichcom




AustriaTel (+43) 1 605 81 10 Fax (+43) 1 605 81 20

BelgiumTel (+32) 3 899 13 01 Fax (+32) 3 899 13 11



ChileTel (+56) 2 495 7395 Fax (+56) 2 495 7396



DenmarkTel (+45) 43 56 59 00 Fax (+45) 43 56 59 05

FinlandTel (+358) 9 350 9250 Fax (+358) 9 350 92555



HungaryTel (+36) 1 235 9055 Fax (+36) 1 235 9068






JapanTel (+81) 3 5796 7300 Fax (+81) 3 5796 7315



MalaysiaTel (+60) 3 5635 3321 Fax (+60) 3 5635 4116



NorwayTel (+47) 23 17 60 00 Fax (+47) 23 17 60 10

PolandTel (+48) 61 829 01 00 Fax (+48) 61 829 01 20


RussiaTel (+7) 495 621 5828 Fax (+7) 495 621 6037


SlovakiaTel (+421) 255 571 562 Fax (+421) 255 571 564



SwedenTel (+46) 8 742 4200 Fax (+46) 8 742 4243


ThailandTel (+66) 2 126 8141 Fax (+66) 2 126 8080



VietnamTel (+84) 8 3516 2810 Fax (+84) 8 6258 4238


neurodegenerative diseases (13 mb )

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