early-onset forms of

Parkinson’s disease

Dr. Pupak Derakhshandeh Dr. Pupak Derakhshandeh (PhD)(PhD)

Assis. Prof. Med. Sci. of Tehran Assis. Prof. Med. Sci. of Tehran UnivUniv.

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Parkinson's Disease

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Parkinson's Disease

one of the most common human neurodegenerative diseases

progressive affecting one of the regions of the brain

controlling movement

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The most common symptoms

Tremor

muscular stiffness

and slowness of movement

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there are different types of parkinsonism

the most common condition today is the one first recognized in 1817 by James Parkinson

At present there is no cure

but treatments do exist and are available

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Dopamine

symptoms are due to a deficiency of the brain chemical:

Dopamine the nerve cells containing dopamine: die

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Dopamine

As a chemical messenger, and is similar to adrenaline

Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain

Regulation of dopamine: plays a crucial role in our mental and physical health

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Dopamine in substantia nigra

Neurons containing the neurotransmitter dopamine are clustered in the midbrain

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L-DOPAIn Parkinson's disease, the

dopamine- transmitting neurons in this area die.

To help relieve their symptoms, we give these people L-DOPA, a drug that can be converted in the brain to dopamine

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Dopamine - A Neurotransmitter

One of the neurotransmitters playing a major role in addiction is dopamine

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Addiction and dopamine

In certain areas of the brain when dopamine is released

it gives one the feeling of pleasure or satisfaction person will grow a desire for the satisfaction To satisfy that desire the person will repeat

behaviors that cause the release of dopamine For example food, smoke,… release dopamine these behaviors can result in addiction due their

effect on dopamine!

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How the addiction begins? e.g. Cocaine

Cocaine chemically inhibits the natural dopamine cycle

after dopamine is released, it is recycled back into a dopamine transmitting neuron

cocaine binds to the dopamine and does not allow it to be recycled it floods certain neural areas The flood ends after about 30 minutes the person is left yearning to feel as he or she once

did person is constantly trying to repeat the feeling that

he or she had the first time

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How the addiction begins?

After the first time, the person expects the effect, thus less dopamine is released the experience is less satisfying

because dopamine is also released when something pleasurable yet

unexpected occurs!

This principal is the foundation of why gambling releases dopamine!

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incidence

The incidence of Parkinsonism increases with age

and is uncommon in people younger than forty Parkinson's disease affects both men and

women across all ethnic groups and is a serious

health problem in all the world

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1-I) Slowness of movement

This is the most disabling symptom

The slowness makes it difficult to get out of a chair or turn in bed

Fine movements such as buttoning clothing, handwriting, and using a fork or knife may become difficult

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1-II) Slowness of movement

Later, the person appears to be in slow motion and if not treated may become virtually frozen like a statue

Because of the enormous energy it takes to overcome slowness, the person with Parkinson's disease often complains of being "weak" although there is no true muscular weakness

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2) Tremor

Tremor or shaking occurs in about two-thirds of people with Parkinsonism

the most visible and obvious sign of the disease

Parkinson tremor usually affects the hands and feet

it sometimes involves the lips, tongue, and jaw

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3) Muscle stiffness

Stiffness combined with slowness

may cause aching muscles and joints,

especially in the shoulders

This is sometimes misinterpreted as "arthritis" or "bursitis”

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4) Masked face

showing little or no emotion through facial expression

Blinking and spontaneous eye movements are less frequent

This can be misinterpreted as lack of interest or depression

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5) Walking difficulties

The gait may be slow with short steps

It is common to have difficulties with balance

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6) Speech problems

About one half of all individuals with Parkinson's disease develop difficulty with their speech

Communication can be complicated further by a fast mumbling speech with uncontrollable repetitions of the first syllable

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7) Swallowing difficulties

difficulty eating because their ability to swallow has become impaired

Food may collect in the mouth or the back of the throat resulting in choking or coughing

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Parkinson’s disease in the family

synuclein gene

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Alpha-synuclein

Alpha-synuclein is part of the synuclein family including beta- and gamma-synuclein

Synucleins are very common in the brain

SNCA located on chrmosome 4

expresses the140-amino acids (OMIM*163890)

(http://health.upenn.edu/cndr/research1/tausyn/tausyn.htm)

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Familiar Parkinsons

No alterations in alpha-synuclein gene dosage observed in sporadic Parkinsons

(Movement disorders disease : official journal of the Movement Disorder Society. 2006 Mar 21)

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Synuclein (SNCA)

point mutations seen in familial Parkinson's disease (PD)

are rarely found in sporadic diseaseusually develop symptoms around

age 45 (AD)

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Familiar Parkinson’s disease

Parkinson’s disease in familiar except for its:

early onset a larger than expected number of people

with Parkinson’s disease

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Lewy bodies

similar to the beta-amyloid plaques found in Alzheimer's / and PD patients  

The Lewy bodies lead to loss of neurons

then dopamine (a neurotransmitter)

and finally loss of motor control

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defected alpha-synuclein product the primary component of Lewy bodies in all

PD patients two different a-synuclein missense

mutations (A30P and A53T) are associated with: rare, autosomal dominant early-onset PD and have been shown to

form fibrils

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PD-linked mutations (A30P and A53T)

correlated to the onset of disease phenotype

in vitro a-synuclein oligomerization:suggesting that the process of a-

synuclein fibrillization may initiate neurodegeneration

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Synuclein (SNCA)

synuclein mRNA expression : play a role in the etiology of the disease

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Exception:Movement Disorders, Vol. 20, No. 5, 2005

study demonstrates that -synuclein expression

levels were not significantly different between sporadic PD and healthy controls similar in age, gender, and race.

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Dosage effect on clinical phenotype

even in the absence of mutations detectable by sequence analysis

simple multiplications of SNCA can cause autosomal dominant forms of PD

a dosage effect on clinical phenotype, with duplication of the gene resulting in a phenotype similar to PD

but triplication resulting in early-onset parkinsonism with dementia

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neither mutations in the coding region of SNCA

nor over expression of the gene due to multiplication

appear to be common causes of PD

It remains possible: other genetic factors may influence -

synuclein mRNA expression play a role in the etiology of the disease

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an association between the polymorphic sequence repeat in the promoter region of SNCA and PD risk

(Mellick GD, Maraganore DM, Silburn PA. Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci Lett 2005; 375: 112-116. )

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mitochondrial dysfunction

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The role of mitochondrial dysfunction in Parkinson's disease

functions of DJ1, PINK1 and OMI/HTRA2 which are all associated with the mitochondria

in cellular protection against oxidative damage

(Nature Reviews Neuroscience 7, 207-219 (March 2006) |

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Familial forms of PD

11 genetic loci with linkages to PD have been established, and for six of these (PARK 1/4, 2, 6, 7, 8, and 9), the responsible gene has been identified

conclusively determined to cause familial

forms of PD (Ramirez et al. 2006)

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PARK7 (AR)

DJ-1, and several point mutations in this part of PARK 7 gene have been associated with an autosomal recessive early onset form of PD

(Tang et al. 2006).

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The DJ-1 mutated protein

encodes a ubiquitous, highly conserved protein

DJ-1 mutations are associated with PARK7 a monogenic form of human

PARKINSONISM The function of the DJ-1 protein:

in the oxidative stress response loss of DJ-1 function leads to

neurodegeneration& PARKINSON's disease

(Science 10 January 2003:Vol. 299. no. 5604, pp. 256 – 259)

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PARKINSON DISEASE 6,

AUTOSOMAL RECESSIVE

EARLY-ONSET; PARK6

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PARK6

Localization of a novel locus for autosomal recessive early-onset parkinsonism:

on human chromosome 1p35-p36

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PARK6

unrelated families with autosomal recessive PD from various regions in Asia that showed linkage to the PARK6 locus

Families: consanguineous

Age at onset ranged from 18 to 56 years, although most had onset in the third or fourth decades

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Autosomal recessive PD from

mutations affecting the PINK1 kinase domain in PARK6 families

onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations

(Hatano et al., 2004 ; Healy et al., 2004 ; Rogaeva et al., 2004 ; Rohe et al., 2004 ; Valente et al., 2004a ; Valente et al., 2004b ; Bonifati et al., 2005 ; Klein et al., 2005)

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pedigrees of families with PINK1 mutations (AR)

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PINK1 mutations

All missense (C125G, E240K, L369P, G386A and G409V) mutations replace highly conserved residues

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Relative frequencies of patients with PINK1 or parkin mutations and

without PINK1 and parkin mutations according to the age at onset

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PINK1 mutations

that heterozygous mutations in genes (compound heterozygous):

autosomal recessive forms with an early onset can also cause later onset Parkinson's disease !

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An Exception !

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A) novel homozygous nonsense PINK1 mutation in exon 3(C99A) leading to a loss of kinase domain of the PINK1 protein (Tyr258Stop).

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B: A novel heterozygous missense mutation in the kinase domain of exon 4 (G62A) leading to an amino acid substitution (Ala280Thr).

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Molecular Findings in Familial Parkinson Disease Park2 gene (AR) Mutations in Park2 gene account for 38% of

the families with recessive parkinsonism in Spain

Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood

(Arch Neurol. 2002;59:966-970)