causes and consequences of microrna dysregulation in neurodegenerative diseases

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Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases Lin Tan & Jin-Tai Yu & Lan Tan Received: 13 May 2014 /Accepted: 22 June 2014 # Springer Science+Business Media New York 2014 Abstract Neurodegenerative diseases, including Alzheimers disease (AD), Parkinsons disease (PD), Huntingtons disease (HD) and amyotrophic lateral sclerosis (ALS), originate from a loss of neurons in the central nervous system (CNS) and are severely debilitating. The incidence of neurodegenerative dis- eases increases with age, and they are expected to become more common due to extended life expectancy. Because of no clear mechanisms, these diseases have become a major chal- lenge in neurobiology. It is well recognized that these disor- ders become the culmination of many different genetic and environmental influences. Prior studies have shown that microRNAs (miRNAs) are pathologically altered during the inexorable course of some neurodegenerative diseases, sug- gesting that miRNAs may be the contributing factor in neu- rodegeneration. Here, we review what is known about the involvement of miRNAs in the pathogenesis of neurodegen- erative diseases. The biogenesis of miRNAs and various functions of miRNAs that act as the chief regulators will be discussed. We focus in particular on dysregulation of miRNAs which leads to several neurodegenerative diseases from three aspects: miRNA-generating disorders, miRNA-targeting genes and epigenetic alterations. Furthermore, recent evi- dences have shown that circulating miRNA expression levels are changed in patients with neurodegenerative diseases. Circulating miRNA expression levels are reported in patients in order to evaluate their application as biomarkers of these diseases. A discussion is included with a potential diagnostic biomarker and the possible future direction in exploring the nexus between miRNAs and various neurodegenerative diseases. Keywords Alzheimers disease . Parkinsons disease . Huntingtons disease . Amyotrophic lateral sclerosis . MicroRNA Introduction Neurodegenerative diseases are a group of typically late- onset, progressive disorders that lead to cognitive and/or movement disorders. Some of the most studied include Alzheimers disease (AD), Parkinsons disease (PD), amyo- trophic lateral sclerosis (ALS) and Huntingtons disease (HD). For the past decades, it has been thought that neurodegenera- tive diseases are caused by genetic and/or epigenetic alter- ations to protein-coding genes. These alterations result mainly from somatic genetic events that occur over long periods of time [1]. These findings have informed the development of novel therapies that are based on the specific genetic alter- ations which are involved in neurodegenerative pathogenesis [2]. Although progress has been made in identifying the genetic and epigenetic causes, several challenges remain. In mammalian cells, mRNA levels and protein levels tend to correlate quite poorly [3]. This may be because translation (RNA to protein) is even more important than transcription (DNA to RNA) as a nidus for gene expression regulation. More than 95 % of human cellular RNAs are noncodingRNAs, that is, other than mRNAs, and most of these mole- cules participate in translational regulation [4]. These and other data have led researchers to seek a better understanding of mRNA translation [5]. In 1993, Victor and colleagues discovered a gene, lin-4, that affected development in Caenorhabditis elegans and L. Tan : J.<T. Yu : L. Tan College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China L. Tan : J.<T. Yu (*) : L. Tan (*) Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China e-mail: [email protected] e-mail: [email protected] Mol Neurobiol DOI 10.1007/s12035-014-8803-9

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Causes and Consequences of MicroRNA Dysregulationin Neurodegenerative Diseases

Lin Tan & Jin-Tai Yu & Lan Tan

Received: 13 May 2014 /Accepted: 22 June 2014# Springer Science+Business Media New York 2014

Abstract Neurodegenerative diseases, including Alzheimer’sdisease (AD), Parkinson’s disease (PD), Huntington’s disease(HD) and amyotrophic lateral sclerosis (ALS), originate froma loss of neurons in the central nervous system (CNS) and areseverely debilitating. The incidence of neurodegenerative dis-eases increases with age, and they are expected to becomemore common due to extended life expectancy. Because of noclear mechanisms, these diseases have become a major chal-lenge in neurobiology. It is well recognized that these disor-ders become the culmination of many different genetic andenvironmental influences. Prior studies have shown thatmicroRNAs (miRNAs) are pathologically altered during theinexorable course of some neurodegenerative diseases, sug-gesting that miRNAs may be the contributing factor in neu-rodegeneration. Here, we review what is known about theinvolvement of miRNAs in the pathogenesis of neurodegen-erative diseases. The biogenesis of miRNAs and variousfunctions of miRNAs that act as the chief regulators will bediscussed.We focus in particular on dysregulation of miRNAswhich leads to several neurodegenerative diseases from threeaspects: miRNA-generating disorders, miRNA-targetinggenes and epigenetic alterations. Furthermore, recent evi-dences have shown that circulating miRNA expression levelsare changed in patients with neurodegenerative diseases.Circulating miRNA expression levels are reported in patientsin order to evaluate their application as biomarkers of thesediseases. A discussion is included with a potential diagnostic

biomarker and the possible future direction in exploring thenexus between miRNAs and various neurodegenerativediseases.

Keywords Alzheimer’s disease . Parkinson’s disease .

Huntington’s disease . Amyotrophic lateral sclerosis .

MicroRNA

Introduction

Neurodegenerative diseases are a group of typically late-onset, progressive disorders that lead to cognitive and/ormovement disorders. Some of the most studied includeAlzheimer’s disease (AD), Parkinson’s disease (PD), amyo-trophic lateral sclerosis (ALS) and Huntington’s disease (HD).For the past decades, it has been thought that neurodegenera-tive diseases are caused by genetic and/or epigenetic alter-ations to protein-coding genes. These alterations result mainlyfrom somatic genetic events that occur over long periods oftime [1]. These findings have informed the development ofnovel therapies that are based on the specific genetic alter-ations which are involved in neurodegenerative pathogenesis[2]. Although progress has been made in identifying thegenetic and epigenetic causes, several challenges remain. Inmammalian cells, mRNA levels and protein levels tend tocorrelate quite poorly [3]. This may be because translation(RNA to protein) is even more important than transcription(DNA to RNA) as a nidus for gene expression regulation.More than 95 % of human cellular RNAs are “noncoding”RNAs, that is, other than mRNAs, and most of these mole-cules participate in translational regulation [4]. These andother data have led researchers to seek a better understandingof mRNA translation [5].

In 1993, Victor and colleagues discovered a gene, lin-4,that affected development in Caenorhabditis elegans and

L. Tan : J.<T. Yu : L. TanCollege of Medicine and Pharmaceutics, Ocean University of China,Qingdao, China

L. Tan : J.<T. Yu (*) : L. Tan (*)Department of Neurology, Qingdao Municipal Hospital, School ofMedicine, Qingdao University, Qingdao, Chinae-mail: [email protected]: [email protected]

Mol NeurobiolDOI 10.1007/s12035-014-8803-9

found that its product was a small non-protein-coding RNA[6]. After a series of seminal findings, these small noncodingmicroRNAs (miRNAs) have revealed an intriguing additionallevel in fine-tuning the genome [7]. The transcriptome isutilized continuously in different combinations, for instanceto generate the complex cellular networks of the brain bymodulating the expression of thousands of genes and contrib-ute to widely varied physiological processes [8]. Sequencevariants which were associated with HD affected miRNAbinding the BDNF [9, 10] and changes in miRNA expressionprofiles in AD [11–13] and PD [14] patients are examples ofmiRNAs potentially involved in neurological disease [15, 16].Understanding the fundamental aspects of miRNA neurobiol-ogy and the possible clinical implications related to miRNAdysfunction are clearly important for many fields ofneuroscience.

Biology of miRNAs

The biogenesis and actions of miRNAs are increasingly wellinvestigated. Like some classical protein-coding genes,miRNA genes are also embedded in the genome [7]. Theyare transcribed by RNA polymerase II [17] (some miRNAsare transcribed by RNA polymerase III [18]) as well. Thehuman genome harbors hundreds of miRNAs (miR-base19.0). The genomic location of miRNAs varies and can befound in both intragenic and/or intrinsic regions of protein-coding transcripts. In the nucleus, primary miRNA transcripts(pri-miRNA) are processed by the Drosha-DGCR8 enzymecomplex to generate a 70 nucleotide stem loop precursormiRNA (pre-miRNA) [19]. The pre-miRNA is transportedto the cytoplasm via exportin 5 where it is cleaved by the typeIII Dicer to generate mature double-stranded miRNAs [20].MiRNAs are 19–24 nt single-stranded RNA molecules thatinhibit gene expression by binding to a complementarysequence in the 3′UTR of target genes [21]. Only oneof the two strands is loaded into the RNA-inducedsilencing complex (RISC) that identifies target mRNAbased on sequence complementarity with the miRNA[22]. One of the core components of RISC is themember of the Argonaute (Ago) protein family, in par-ticular Ago1 and Ago2. RISC controls gene expressionby binding via imperfect complementarity to the 3′UTRof target mRNAs leading to degradation of the mRNAwhen there is sufficient complementarity or translationalrepression of protein expression [23, 24] (Fig. 1).However, miRNAs control the translational repressionby targeting numerous mRNAs. As a matter of fact,miRNAs provide an intricate network of regulation thatresult in fine tuning, robustness and additional complex-ity of the transcriptome and proteome.

The Discovery of miRNA in Neurodegeneration

Neurodegeneration is characterized by the progressive loss ofneurons during the normal course of brain development in thenervous system. Understanding the main cause of cell dys-function and death in many neurodegenerative diseases is achallenging task that might also provide important insightsinto the mechanisms of neurodegeneration. To date, the in-volvement of miRNAs in a variety of physiologically relevantprocesses in neurodegeneration has been firmly established [5,25, 26]. Earlier work demonstrated an abundant and particu-larly diverse source of miRNAs is present in the brain, someof which follow a specific pattern of expression during braindevelopment [8, 27, 28]. The profound single miRNA canalso be regulators of important biological pathways. In addi-tion, a functional role for miRNAs in the more specific neu-rological processes is also emerging, and their dysfunctioncould have direct relevance for our understanding of neurode-generative disorders [29]. Here in our review, three mainprogresses have been used to study the causes of miRNAson neurodegeneration. First is the disruption of propermiRNA biogenesis (Fig. 1). Second is the identification ofmiRNAs that target specific disease genes and their variations.The last is the epigenetic alterations in brain. Here, we de-scribe below the causes and consequences of miRNAs inneurodegenerative diseases.

MiRNA-Generating Disorders in NeurodegenerativeDiseases

Dicer

A functional link between miRNAs and neurodegenerativedisorders is discovered in studies of the effect of globaldisruption of miRNA biogenesis including disturbance inDicer, Drosha, and RISC. Dicer, a member of the RNase IIIfamily of nucleases that cleave double-stranded RNAs, is oneof the key enzymes in miRNA biogenesis [30]. Dicer isrequired to cleave pre-miRNAs and generate a ~22 ntmiRNA duplex that is incorporated into RISC [20, 30, 31].In the absence of Dicer, miRNAs are not produced properly.In most cases, genetic ablation of Dicer was used to reduce orabolish the production of mature miRNAs in the cell or tissueinvestigated. Overall, all these models display a progressiveneuronal loss, which are accompanied by behavioral and/ormemory deficits. In mice, for instance, deletion of Dicer inpostmitotic midbrain dopamine neurons causes a progressiveloss of those cells, suggesting an essential role of miRNAs inthe differentiation or maintenance of dopamine neurons. Agood candidate for this is miR-133b, which is enriched inmidbrain and deficient in PD patients or PD animal models.Loss of miR-133b seems to increase dopamine release slightly

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in cell cultures, suggesting a subtle role in dopamine neuralfunction [32]. Notably, alterations in neurons in other parts ofbrain which could have profound effects on memory are alsoobserved in Dicer-deficient mouse models. Smith et al. creat-ed a forebrain-specific Dicer conditional knockout mouse inwhich postmitotic neurons were characterized as having in-creased levels of APP isoforms to investigate the involvementof miRNAs in the regulation of APP splicing. As miR-124plays a pivotal role in neuronal maintenance and splicing [33,34], Smith et al. induced the increased expression of miR-124in Neuro2a cells, which was enough to induce the skipping of

exons 7 and 8 by inhibiting poly-pyrimidine tract bindingprotein 1 (PTB1). Supporting this observation, lower expres-sion of miR-124 was also measured in the brains of ADpatients [35].

The essential role of Dicer in CNS is also reflected in theloss of Dicer-1. As the key enzyme of miRNA biogenesis inDrosophila, Dicer-1 dramatically enhances neurodegenera-tion by a mutant form of the spinal cerebellar ataxia type 3(SCA3). The loss of Dicer-1 could prevent apoptosis and thensuppress degeneration owing to the absence of miRNAs [36].Consistent with this notion, selective genetic ablation of Dicer

Fig. 1 MiRNA (dys)regulation network in neurodegenerative diseases.The miRNA genes are transcribed by RNA polymerase to produceprimary transcripts (pri-miRNA) that resemble in classical mRNA. Thesetranscripts are further processed in the nucleus by Drosha enzyme togenerate a hairpin-like precursor miRNA (pre-miRNA). Once exported tothe cytoplasm by exportin 5, the pre-miRNA was sheared by Dicer. Itproduces the mature miRNA (red curve). Combined with the RNA-induced silencing complex (RISC) complex, which composes Ago1and Ago 2 protein, the miRNA complex binds the 3′UTR of targetmRNA (blue curve). This leads to posttranscriptional inhibition or deg-radation. The disorders in miRNA generation play role in neurodegener-ative diseases, including absence of Dicer. The absence of Dicer contrib-utes to Aβ accumulation and dopamine loss. Trans-activating response

region DNA-binding protein (TDP-43) could combine with Drosha and itcould be seen in ALS models. In miRNAs biogenesis process, themutated form of leucine-rich repeat kinase2 (mut-LRRK2) is closelyinvolved with PD. This is due to the fact that mut-LRKK2 physicallyinteracts with Ago1 and Ago2—two components of the RISC. In HD,mutant Huntington gene (Htt) inhibits the formation of processing bodiesby interacting with Ago and Ago2. Pri-miRNA primary miRNA, Pre-miRNA precursor miRNA, RISC RNA-induced silencing complex, TDP-43 trans-activating response region DNA-binding protein, mut-LRRK2mutated form of leucine-rich repeat kinase2,PD Parkinson’s disease, ALSAmyotrophic lateral sclerosis, HD Huntington’s disease, Htt Huntingtongene

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in Purkinje cells leads to cerebellar degeneration and ataxia[37]. Moreover, in miR-8 mutant flies, the increased expres-sion of the transcriptional regulator Atrophin increases apo-ptosis in the nervous system [38]. Dendritic spines and post-synaptic densities are enriched in Dicer, raising the possibilitythat it also participates in synaptic development and plasticity[39]. However, the underlying mechanisms may be compli-cated. Despite the canonical miRNA pathway, Dicer is alsorequired to generate mirtron that novel ~22 nt small RNAs areprocessed from short intrinsic hairpins [40]. Unlike the canon-ical process, mirtrons are generated independently of Drosha.The involvement of Dicer in other processes, such as process-ing of other endogenous double-stranded RNAs, also remainsto be further elucidated in various models [41]. Therefore,neurodevelopmental defects as a result of the global loss ofDicer activity need to be interpreted with caution. For thisreason, using loss-of-function approaches to understand thefunctions of specific miRNAs in different aspects of neuronaldevelopment may prove to be more informative. RemovingDicer is conceptually a crude experimental approach, but theresults of these early experiments support the hypothesis thatdefects in the miRNA regulatory network in the brain are thepotential cause of neurodegenerative disease.

Drosha

Moreover, Drosha complex is discovered to be associatedwith trans-activating response region DNA-binding protein(TDP-43) which is familiar in both sporadic and familialALS patients [42]. Besides, mutations in RNA binding pro-tein—fused in sarcoma/translocated in liposarcoma (FUS/TLS) are also found in ALS patients. Similar to TDP-43,FUS/TLS protein binds to pre-mRNA molecules and deter-mines their fate via regulating splicing, transport, stability, andtranslation. Recently, it has been shown that FUS/TLS pro-motes biogenesis of specific miRNAs via recruiting Drosha toprimary miRNA transcripts [19]. Regarding FUS/TLS, itsdownregulation in neuroblastoma cell line affects the biogen-esis of miRNAs. In fact, FUS/TLS is recruited at the chroma-tin, where it directly binds pri-miRNAs, facilitating Droshaloading.

RISC

In miRNAs biogenesis process, components of RISC partic-ipate in neurodegeneration. Investigations in flies have dem-onstrated that the mutated form of leucine-rich repeat kinase2(mut-LRRK2) which is closely involved with PD is responsi-ble for a reduced miRNA-mediated gene repression. This isdue to the fact that mut-LRKK2 physically interacts withAgo1 and Ago2—two components of the RISC—inducingtheir downregulation in aged Drosophila melanogaster [43].In HD, the mutant Huntington gene (Htt) inhibits the

formation of processing bodies (P bodies) by interacting withAgo and Ago2, which are involved in miRNA biogenesis[44]. Thus, miRNA dysregulation is expected in the brain ofHD patients.

MiRNA-Targeting Genes in Neurodegenerative Diseases

Neurodegenerative diseases can be roughly classified in twoforms: the familial forms that are associated with geneticmutations, such as HD, familiar AD, and some forms of PD;and the sporadic forms, for which in many cases the cause isnot clearly known, e.g., sporadic AD, ALS, and sporadic PD.Despite this distinction, there are alsomounting evidences thatsporadic neurodegeneration is a combination of genetic pre-disposition and environmental factors with overlapping dis-ease mechanisms as seen in the familial disease forms [45].Recent observations support the disease-compromised cells inneurodegeneration exhibit profound dysregulation of geneexpression. Gene-dosage effects are clearly implicated in neu-rodegenerative disorders. MiRNAs are small regulatoryRNAs that act in a complex web of interactions with targetmRNAs to shape the cellular protein landscape by posttran-scriptional control of mRNA decay and translation. Theysubject to numerous regulatory mechanisms including generegulation. Endogenously transcribed genes may act in largecomplex networks in conjunction with miRNAs to regulatethe output of protein [46]. Thus, miRNAs introduce a novelconcept of regulatory control over gene expression and thereare increasing evidences that they play a profound role inmultiple aspects of disease pathogenesis.

MiRNA-Targeting Genes in AD

In sporadic AD, clinical and research evidence indicates thataberrant regulation of miRNA-dependent gene expression isclosely associated with molecular events responsible for am-yloid β peptide (Aβ) production, NFT formation, and neuro-degeneration. Some genome-wide-associated miRNAs(GWSM) studies revealed some insight into these possiblemechanisms. MiR-106a, -520c, -106b, and miR-17-5p coulddownregulate amyloid beta precursor protein (APP) geneexpression in vitro [26, 47], but only miR-106b expressionwas found in sporadic AD patients [48]. Additional evidencefor possible miRNA functions in AD was recently providedfrom the APPswe/PSΔE9 transgenic mice, which contain amouse-human hybrid of the APP gene with the Swedishmutation K594N/M595L [49] and the PS1ΔE9 transgene thatencodes the exon-9-deleted human presenilin-1 [50]. In thisstudy, miR-34a was functionally linked to downregulation ofbcl2 expression, an anti-apoptotic protein involved in theregulation of the apoptotic proteins caspase 9 and 3. The

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researchers demonstrate that miR-34a indirectly regulates cas-pase 3 by targeting bcl2 and this correlated with an increasedexpression of miR-34a and caspase 3 in the cortices of thetransgenic mice. These results indicated an involvement ofmiRNAs in the apoptotic signaling pathway, which is relevantin AD [51]. BACE1, insulin-like growth factor 1 (IGF-1), andserine palmitoyltransferase (SPT) influence APP expressionand are modulated by miRNAs. Decreased miR-29a and miR-29b-1 in AD patients correlated with increased β-site APPcleaving enzyme 1 (BACE1) expression. Since BACE1 is atarget for both miRNAs and the rate-limiting enzyme for Aβproduction, these results could imply correlative evidence fora mechanism in AD. Similarly, another study demonstrateddiminished miR-107 expression in cortices from AD pa-tients and biochemical analyses showed that BACE1 wasa target for miR-107 [52]. Supportive information camealso from a mouse model of AD, in which miR-298 and -328 could be identified as targeting miRNAs for BACE1[49]. Besides, SPT is increased in the brain of sporadicAD patients with upregulation of several miRNAs, includ-ing miR-137, miR-181c, miR-9, miR-29a, miR-29b-1, andmiR-15. Direct inhibition of SPTLC1 by miR-181c andmiR-137 as well as direct inhibition of SPTLC2 by miR-29a, miR-29b, and miR-9 were confirmed by in vitroluciferase assay [53]. However, in familial Alzheimer’sdisease, dominant mutations in the genes encoding forpresenilin (PSEN1 and PSEN2) are the most commoncause [54]. PSEN2 knockout mice and microglia modelsuggested miR-146 is a potent negative regulator of innateimmunity. This observation suggested that PSEN2 modu-lates cytokine responses via inhibition of miR-146. In linewith this evidence, the target mRNA of miR-146ainterleukin-1 receptor-associated kinase-1 (IRAK-1) wasincreased in PS2KO microglia. Jayadev also strongly dem-onstrated that PSEN2 influences microglia activity but theexact mechanism by which PSEN2 carries out this taskvia miR-146 modulation still need to be elucidated [55].

In the case of AD, tau is hyper-phosphorylated andaccumulating in the cytoplasm where it gives origin tointra-neuronal protein aggregates known as NFTs. Todate, researchers found several miRNA-binding sitesand they were able to validate direct inhibition of hu-man tau by miR-34a [56]. Another approach to inhibitNFT formation is represented by regulating the phos-phorylation status of tau protein. MiR-26b was identi-fied to be increased in the substantia nigra at earlystages of AD and remains elevated in AD brain. Atarget mRNA of miR-26b was confirmed to beRetinoblastoma (Rb). Both overexpression of miR-26band downregulation of Rb in primary cortical neuronsshowed activation of cyclin-dependent kinase 5 (Cdk5)and enhanced tau phosphorylation, followed by apopto-sis and neurodegeneration in vitro [57].

MiRNA-Targeting Genes in PD

PD is a complex polygenetic disorder. To investigate miRNA-mediated gene regulation, miR-base was used to predict hu-man miRNA target sites on selected 29 genes related to PD.Overall, convergence of results predicted by two algorithmsrevealed that 48 target sites for midbrain-specific miRNAoccur in close proximity in nine genes [58]. However, so far,six miRNAs have been widely recognized to be associatedwith the dopaminergic phenotype in PD: (1) miR-133b thatregulates the transcriptional activator Pitx3, which was a keyfactor in the development of the DA neuronal phenotype inmice. Furthermore, miR-133b was also upregulated in spo-radic PD patients [32]. (2) miR-7, which was shown to sup-press α-Synuclein in human neuroblastoma cells. It could besuppressed by oxidative stress in vitro and in vivo. Sincedysfunctional α-Synuclein has been implicated in a majormechanism in PD pathogenesis, oxidative stress might influ-ence α-Synuclein levels via miR-7 inhibition [59]. (3) miR-153 was conserved across vertebrate species. It also inhibitedα-Synuclein [59, 60]. (4) miR-433 was linked to a mutation ofits binding site in the 3′UTR region of the FGF20 gene. Aresearcher confirmed that miR-433 could inhibit the transla-tion of the FGF20 gene in vitro. As a significant correlation ofPD, SNPs in FGF20 indicates that the genetic variability ofFGF20 can be a PD risk [61]. Wang et al. demonstrated thatSNP rs12720208 avoids inhibition by FGF20 through miR-433. However, so far, no in vivo data were available thatdemonstrate a direct link of functional miR-433 to PD patho-genesis [62]. (5) miR-205, an analysis had showed that trans-fection of miR-205 in the neurons expressing a PD-relatedLRKK2 R1441G mutant prevented the neural outgrowth de-fects [63]. (6) miR-124a regulated the transcriptional activatorFoxA2 which was a key factor in midbrain dopaminergic celldevelopment in both rodents and humans [64, 65] and itsfunction was required for survival of dopaminergic neuronsin PD mice model [66]. However, FoxA2 was not only in-volved in regulating genes for glucose metabolism and insulinsecretion, but was also important for molecules that play a rolein ATP-sensitive K+ channel activity in neuronal homeostasis.Besides, Cho et al. analyzed the expression levels of LRKK2protein in the frontal cortex tissue of eight sporadic PD pa-tients and relative control subjects. The affected brains werecharacterized by higher expression levels of LRRK2 protein,suggesting a miRNA-mediated regulation of this protein [67].

MiRNA-Targeting Genes in HD

HD is a neurodegenerative condition caused by CAG repeatexpansion of the Huntington gene (Htt). HD patients manifestthe cognitive defects and motor control impairment due toneuronal dysfunction characterized by progressive loss ofcortical and striatal neurons. In HD, miR-196a suppresses

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the expression of mutant Htt at the mRNA and protein levels.Furthermore, this inhibition was not due to the direct binding ofmiR-196a to the 3′UTR of mutated Htt. Otherwise, miR-196apredominantly suppressed Htt expression through the inhibitionof protein synthesis and partly through enhanced protein degra-dation. In early-onset HD patients, the deregulation of additionalmiRNAs, including miR-486, miR-196a, miR-17-3p, miR-22,miR-485-5p, miR-500, and miR-222, was found [68]. Besides,miR-100, miR-151-3p, miR-16, miR-219-2-3p, miR-27b, miR-451, and miR-92a were found to be overexpressed as well.Similarly, miR-128, miR-139-3p, miR-222, miR-382, miR-433, and miR-483-3p were decreased in the HD brain [69].Deregulation of miRNAs associated with HD can be attributedto four TFs that are altered in the HD brain; TP53, REST, E2F1,andGATA4 [70]. Htt was demonstrated to interact with repressorelement silencing transcription factor (REST), the essential tran-scriptional repressor also known as neuron-restrictive silencingfactor (NRSF), in neurons [71]. However, in HD patients themutant Htt does not associate with REST, which relocates to thenucleus of HD neurons and represses many of its target genes.One of the target genes of REST is BDNF, which is essential forneuron survival. Based on the presence of REST binding sites inthe genome, miR-29a, miR-124a, miR-132, and miR-330 werefound to be decreased in the cortex of HD model. Among thesemiRNAs, only miR-132 was confirmed in the human samples.In another study, five miRNAs (miR-9, miR-9∗, miR-29b, miR-124a, and miR-132) were significantly different with increasingHD progression. Whether miRNAs correlate with disease pro-gression inHDpatients was analyzed by the expression profile ofpredicted REST-regulated miRNAs in brain samples [68].

MiRNA-Targeting Genes in ALS

MiR-206 was strongly induced, and the upregulation coincidedwith a typical model of ALS that lower limbs of an animalmodel of ALS is a SOD1 transgenic mouse model [72]. It wasfound to induce the secretion of fibroblast growth factor bindingprotein 1 (FGFBP1) which potentiates the effect of FGFs in thepromotion of presynaptic differentiation at the neuromuscularjunction [73] from muscle by inhibiting Histone deacetylase 4(HDAC4) translation. However, it is important to emphasizethat borders are not clearly drawn in complex gene expressionnetworks, as the function of both miRNAs and target genes aremultifaceted and interwoven in the many aspects.

MiRNA in Epigenetic Alterations in NeurodegenerativeDiseases

To date, results from miRNA profiling experiments in post-mortem brain, mouse models or cells suggest that a number ofspecific miRNAs are dysregulated in patients with

neurodegenerative disorders, several of which regulate genesor protein linked to the related pathology either directly, suchas APP, BACE1 or Htt, or indirectly, via their effects onexpression of genes (Fig. 2). However, in many cases, theexpression of miRNAs is associated with epigenetic mecha-nisms, including DNAmethylation and histone modifications,i.e., mechanisms which show striking alterations with agingand in AD, PD [74, 75]. Vice versa, the epigenetic machineryis often subject to regulation by specific miRNAs, herebyproviding multileveled regulatory feedback circuits [76, 77].The term “epigenetic modifications” reflects mitotically heri-table changes in gene expression patterns that are not encodedin the primary DNA sequence. According to reports, epige-netic mechanisms may affect the expression of miRNAs inpathological conditions in a tissue-specific manner. AberrantDNA methylation is a common occurrence in a spectrum ofneurodegenerative diseases, like AD or PD [78–80]. Hyper- orhypo-methylation of miRNA promoters and the consequentchanges in expression of some miRNAs have been linked todisease states [81, 82]. Moreover, the observation of distinctdisease- and tissue-specific miRNA methylation patterns sug-gest a miRNA-targeted regulation by DNA methylation,which may occur to a comparable extent as other gene-specific DNA methylation alterations in AD or PD [83, 84].Previous studies have furthermore implicated a variety ofDNA methylation-specific Methyl-CpG-binding domain pro-teins (MBDs) in the transcriptional regulation of miRNAs [85,86].MBD1 andMethyl-CpG binding protein 2 (MeCP2) havebeen demonstrated to directly modulate the expression ofmiR-137 and miR-184, respectively [87, 88], thus strengthen-ing the hypothesis that DNA methylation is closely involvedin controlling miRNA expression [89, 90]. In the same con-text, histone modifications, especially those of amino-terminaltail domains, are important epigenetic regulators of gene ex-pression. Under specific circumstances, histone modificationsand the associated changes in chromatin structure can affectthe transcriptional levels of miRNAs [91]. From a more gen-eral point of view, we focus our present part on describing theroles of those miRNAs implicated in neurodegenerative dis-eases. The following parts focus on altered miRNAswhich arewell studied in neurodegenerative diseases.

MiRNAs in Epigenetic Alterations of AD

Five miRNAs abundant in AD patients are well investigated:let-7b, miR-9, miR-34, miR-107, and miR-125b. Let-7b hasbeen demonstrated to be increasing in AD patients [92]. Itbelongs to the let-7 miRNA gene family and located onchromosome 22q13.31 [93]. The let-7a-3 gene contains aCpG island and is methylated by DNMT1 and DNMT3B[81]. Among its downstream targets are members of thepolycomb-group proteins involved in chromatin remodeling

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such as Enhancer of zeste homolog 2 (EZH2), and the tran-script of Dicer, which points to a reciprocal interaction be-tween let-7b expression, miRNA maturation and epigeneticregulation [94]. MiR-9 has been observed to be abundantlyexpressed in the fetal hippocampus, while downregulated inAD brain. It is encoded by three different genes which werefound at the loci 1q22, 5q14.3, and 15q26.1, all of whichcontain a CpG island in their promoter region [92, 95].Besides, CpG island hyper-methylation of the miR-34b⁄ccluster appears to modulate p53-mediated miR-34b⁄c expres-sion, while elevated p53 has been indirectly linked to theinduction of tau phosphorylation, one of the profound char-acteristics of AD [96]. In addition, miR-107 expression neg-atively correlates with BACE1 mRNA levels, as observed inAD patients, suggesting miR-107 dysregulation in AD [97].The existence of a CpG island associated with the miR-107promoter and its respective regulation by DNA methylationwas verified by methylation-specific PCR targeting the 5′regulatory region of the miR-107 primary transcript, whichdemonstrates complete loss of methylation upon exposure to5-Aza-2′-deoxycytidine (5-Aza-dC) [98]. MiR-125b is abrain-enriched miRNA and also a probable biomarker ofAD. It is encoded by two genomic loci, miR-125b-1 andmiR-125b-2, which is located respectively on 11q24.1 and21q21.1. Its regulation by DNAmethylation was first reported

in cancer studies [99]. miR-125b is abundantly expressed inthe fetal hippocampus [100], but it has been shown to besignificantly upregulated in AD patients [101]. This has beenproposed to contribute to astrogliosis and to deficits in the cellcycle that are characteristic of degenerating brain tissues[102].

MiRNAs in Epigenetic Alterations of PD

Three miRNAs are reported in epigenetic alterations of PD. Afeedback loop between epigenetic mechanisms and miR-132which may act as negotiators of PD is established via itsrepressive effect on MeCP2 and SIRT1 [103, 104]. It is wellknown that LRRK2 causes sporadic PD while increases thelevel of miR-184 attenuated pathogenic LRRK2 effects [43].Expression of miR-184, a brain-specific miRNA, is repressedby the binding of MeCP2 to its promoter, linking DNAmethylation to miR-184’s activity and its regulatory effectson synaptic plasticity [105]. CREB plays an important role inPD. With regards to its interactions with the classical epige-netic mechanisms, the regulation of CREB expression, a miR-34c target, can be considered as an indirect feedback controlof site-specific histone acetylation. CREB is necessary for theanchoring of CREB-binding protein (CBP), which contains ahistone acetyltransferase (HAT) domain and in turn co-

Fig. 2 The epigenetic miRNA regulatory circuit in neurodegenerativediseases. The epigenetic mechanisms, including DNA methylation andhistone modifications, regulate gene expression by forming a regulatorycircuit associated with miRNAs to maintain normal physiological func-tion. Imbalance of the circuit may lead to the progress of

neurodegenerative disorders, such as AD, PD, HD, and ALS. The blackarrow DNA methylation, the red arrow histone modifications, ADAlzheimer’s disease, PD Parkinson’s disease, HD Huntington’s disease,ALS Amyotrophic lateral sclerosis

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activates CREB to exert its beneficial function towards neu-ronal plasticity [106].

MiRNAs in Epigenetic Alterations of HD

MiR-132 is downregulated in HD mouse model. A feedbackloop between epigenetic mechanisms and miR-132 isestablished via its repressive effect on MeCP2 and SIRT1[103]. However, it needs further research [107, 108].

MiRNAs in Epigenetic Alterations of ALS

MiR-146a is dysregulated in ALS [109]. The genome of miR-146a is situated at 5q34, comprising a CpG island-enrichedpromoter. Treatment with DNMT and HDAC inhibitors sig-nificantly increases miR-146a transcriptional activation byaltering the DNA-binding activity of NF-kB in macrophagesisolated from aged mice, which suggests that DNA methyla-tion and histone acetylation are involved in the regulation ofage-dependent miR-146a expression [88, 110].

Altogether, the discussed findings suggest that the expres-sion of the miRNAs is tightly regulated by epigenetic mecha-nisms, predominantly involving DNA methylation and relatedregulatory proteins. In the majority of cases, miRNAs subse-quently modulate the expression of important epigenetic regu-lators posttranscriptionally, either in a direct or in an indirectmanner, suggestive of a dynamic regulatory circuitry betweenmiRNAs and epigenetic mechanisms at multiple levels.

Applications Role

To date, thousands of human miRNA are known clearlyand novel miRNAs are continuously discovered nowa-days. In practice, most known or novel miRNAs havebeen identified through the use of high-throughput smallRNA sequencing. Global miRNA expression profileshave been well studied in many diseases includingepilepsy [111, 112], stroke [113], and neurodegenerativediseases, and this has stimulated several groups [13, 26,101], including ours [12, 114], to investigate in anunbiased way changes in known miRNA expressionprofiles in sporadic AD patients. Similar studies havebeen performed in sporadic PD, HD, and ALS(Table 1). Therefore, analysis of the known miRNAprofiles might provide interesting diagnostic tools inhumans [16]. Clearly, there is evidence for the knownmiRNAs to be potential biomarkers to aid in the diag-nosis of neurodegenerative diseases.

In this regard, Geekiyanage et al. firstly studied miR-137, -181c, -9, -29a/b connected to AD brain They investigated theexpression levels of these miRNAs in the blood serum of

seven AD patients, seven MCI, and seven controls and iden-tified that these miRNAs were downregulated in AD patients[13]. Sheinerman et al. identified six pairs of brain-enriched plasma miRNA as biomarkers that could differ-entiate MCI patients from healthy controls [115].Moreover, Schipper et al. determined the expression pro-file in peripheral blood mononuclear cells of 16 patientsand 16 controls and identified 4 miRNAs (i.e., miR-34a,181b, 200a, and let-7f) deregulated in this cell type [116].Interestingly, our team previously found that miR-125band miR-181c were downregulated while miR-9 was up-regulated in the AD patients with miR-125b showing highpriority in ROC analysis [12]. Furthermore, we appliedhigh-throughput sequencing through genome-wide serummiRNAs and then identified miR-342-3p as serum bio-marker showing high priority in ROC analysis [114].Despite the blood biomarkers, Cogswell et al. first identi-fied changes in miRNA as biomarkers specific to AD incerebrospinal fluid (CSF) [101]. Another study determinedthat plasma miR-34a and miR-146a levels, and CSF miR-34a, miR-125b, and miR-146a levels in AD patients weresignificantly lower in the control group. On the otherhand, CSF miR-29a and miR-29b levels were significantlyhigher than in control subjects [117]. What is more, cir-culating miRNAs may act as potential biomarkers in PDas well [118]. Next-generation sequencing combing withqRT-PCR was used to measure potential miRNAs in leu-kocytes and 18 miRNAs were discovered with high sen-sitivity and specificity [119]. Besides, some research usingcandidate strategy demonstrated that specific miRNAswere dysregulated in plasma of PD patients [120]. Inaddition, miRNA-based technology plays a pivotal rolein the treatment of Huntington’s disease [121, 124].However, few studies focus on the circulating miRNAsas biomarker of HD and ALS. Limited data showedspecific miRNAs were dysregulated in a small sample ofHD or ALS [122, 123]. Overall, recent studies suggestthat various miRNAs could serve as useful diagnosticbiomarkers for neurodegenerative diseases. The develop-ment of biomarkers of neurodegenerative disorders remainsan unmet challenge, and new approaches that can improvecurrent biomarker strategies are needed. Again, follow-upstudies in large patient cohorts are now needed to assessthe biological and clinical relevance of these findings.

Importantly, novel miRNAs are drawing researchers’ at-tention. In practice, most novel miRNAs have been identifiedthrough the use of high-throughput small RNA sequencing.However, the novel miRNA candidates are specifically butlowly expressed, raising the possibility that not all may befunctional. Interestingly, the majority are evolutionarily youngand overrepresented in the human brain. In a neuronalcell system, the novel miRNAs responded similarly toknown miRNAs when components of the biogenesis

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pathways were knocked down or when the cells wereinduced to differentiate. Almost 300 candidates are ro-bustly expressed in a neuronal cell system and areregulated during differentiation or when biogenesis fac-tors Dicer, Drosha, or Ago2 are silenced [125].

Studies targeting novel miRNAs associated with neurode-generative disorders are limited. Some novel miRNAs wereinvestigated in CSF or serum samples. A study targeting ADor PD discovered 13 novel miRNAs in CSF or serum of thosepatients. Only one novel miRNA (Precursor sequence:aggggccgagggagcgaga_gagcucugcggcgccaag) displayed sig-nificant expression level changes between AD and PD serumsamples [126]. Another experiment concerning ALS charac-terized novel miRNAs from a small RNA library derived fromcontrol and sporadic ALS (sALS) spinal cords. They detected

80 putative novel miRNAs, 24 of which have miRNA re-sponse elements (MREs) within the NEFL mRNA 3′UTR.From this group, they suggested 10 miRNAs were differen-tially expressed in sALS compared to controls. Functionalanalysis by reporter gene assay and relative quantitative RT-PCR showed that two novel miRNAs, miR-b1336, and miR-b2403, were downregulated in ALS spinal cord. They dem-onstrate that the expression of these twomiRNAs (miR-b1336andmiR-b2403) whose effect is to stabilize NEFLmRNA, aredownregulated in ALS. The loss of NEFL steady state mRNAcauses pathology of spinal motor neurons in ALS. Theirresults indicated that there are novel miRNAs expressed inALS spinal cord. They are predicted to target NEFL mRNA[127]. In a word, the novel miRNAs had features similar toknownmiRNAs, but most were evolutionarily young, specific

Table 1 Studies reporting changes in circulating miRNA profiles in neurodegenerative disorders

Pathology Source No. samples(age, sex matched)

No. miRNAsof analysis

Method of analysis Significant miRNAs Reference

AD Serum Case=7;Control=7

5 qRT-PCR Decreased: miR-137, -181c,-9,-29a, -29b

[13]

MCI Plasma Case=30;Control=30

32 qRT-PCR Increased: miR-128, -132,-874,-134, -323-3p, -382

[115]

AD Serum Case=106;Control=22

The total serum miRNAs Next-generationsequencing, qRT-PCR

Various [11]

AD WBC Case=16;Control=16

426 Microarray qRT-PCR Increased: miR-34a,-181b,-200a, let-7f

[116]

AD Serum Case=105;Control=150

6 qRT-PCR Increased: miR-9; Decreased:miR-125b,-181c

[12]

AD Serum Case=208;Control=205

The total serum miRNAs Illumina HiSeq 2000sequencing qRT-PCR

Decreased: miR-98-5p,-885-5p,-483-3p,-342-3p,-191-5p, let-7d-5p

[114]

AD Plasma Case=10;Control=10

6 qRT-PCR Decreased: miR-34a,-146a [117]

AD CSF Case=10;Control=10

201 qRT-PCR Various [101]

AD CSF Case=10;Control=10

6 qRT-PCR Decreased: miR-34a,-125b,-146a;Increased: miR-29a,-29b

[117]

PD Whole blood Case=15;Control=8

6 qRT-PCR Decreased: miR-1,-22,-29;Increased: miR-16-2,-26a

[118]

PD Plasma Case=31;Control=25

7 qRT-PCR Increased: miR-331-5p [14]

PD WBC Case=47;Control=47

The total WBC miRNAs Next-generationsequencing qRT-PCR

Various [119]

PD WBC Case=19;Control=13

18 Microarray,qRT-PCR

Decreased: miR-335,-374,-119a,-126,-151,-29b,-147,-28,-19b,-30c,-29c,-301a,-26

[120]

HD Plasma Case=27;Control=12

2 qRT-PCR Increased: miR-34b [121]

ALS WBC Case=22;Control=26

911 Microarray, qRT-PCR Decreased: miR-451,-1275,-328-5p,-638,-149,-665;

Increased: miR-338-3p

[122]

ALS Serum Case=6;Control=6

11 qRT-PCR Increased: miR-206 [123]

AD Alzheimer’s disease, MCI mild cognitive impairment, WBC white blood cells, qRT-PCR quantitative RT-PCR, CSF cerebrospinal fluid, PDParkinson’s disease, HD Huntington’s disease, ALS amyotrophic lateral sclerosis

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in expression, and overrepresented in the human brain.However, present evidence concerning novel miRNAs stillremain to be discovered for their future application.

Future Projections

Many neurodegenerative diseases such as AD, PD, HD, andALS are characterized by slow development with a longasymptomatic period followed by a stage with clinical symp-toms. As a consequence, these serious pathologies are diag-nosed late in the course of a disease, when pathomechanismshave already occurred. Traditionally, genetic and environmen-tal factors can contribute to the development of neurodegen-erative diseases. MiRNAs are known for their roles in normaldevelopment and function of the central nervous system. Theyare involved in targeted gene expression and act as key regu-lators in several neuroprotective mechanisms. It is a well-established fact that dysregulation of miRNAs eventuallyleads to the development of various neurodegenerative dis-eases [5]. Furthermore, alterations in the patterns of miRNAexpression will probably serve as diagnostic biomarkers ofbrain function, and the initiation and progression of neurode-generative diseases. Thus, applications of circulating miRNA-based tests for diagnosis of acute and chronic brain patholo-gies, for research of neurodegenerative disease are in greatneed. Further research in miRNA expression patterns andprofiling will result in the discovery of many more novelbiomarkers. An in-depth study to determine the functions ofmiRNAs in RNA-mediated gene regulation is likely to remainan area of intense research interest.

Acknowledgments This work was supported in part by grants from theNational Natural Science Foundation of China (81000544, 81171209,81371406), the Shandong Provincial Natural Science Foundation, China(ZR2010HQ004, ZR2011HZ001), and the Shandong Provincial Out-standing Medical Academic Professional Program.

Conflicts of interest The authors declare no conflicts of interest.

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