review article noncoding rnas in neurodegenerative...

Hindawi Publishing CorporationISRN NeurologyVolume 2013 Article ID 375852 5 pageshttpdxdoiorg1011552013375852

Review ArticleNoncoding RNAs in Neurodegenerative Diseases

Shraddha D Rege1 Thangiah Geetha12 Satyanarayana R Pondugula3 Claire A Zizza1

Catherine M Wernette1 and Jeganathan Ramesh Babu1

1 Department of Nutrition Dietetics and Hospitality Management Auburn University Auburn AL 36849 USA2Department of Physical Sciences Auburn University at Montgomery Montgomery AL 36117 USA3Department of Anatomy Physiology and Pharmacology Auburn University Auburn AL 36849 USA

Correspondence should be addressed to Jeganathan Ramesh Babu jeganrbauburnedu

Received 27 February 2013 Accepted 10 April 2013

Academic Editors A Conti and T Muller

Copyright copy 2013 Shraddha D Rege et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Noncoding RNAs are widely known for their various essential roles in the development of central nervous system It involvesneurogenesis neural stem cells generation maintenance and maturation neurotransmission neural network plasticity formationof synapses and even brain aging and DNA damage responses In this review we will discuss the biogenesis of microRNA variousfunctions of noncoding RNArsquos specifically microRNAs (miRNAs) that act as the chief regulators of gene expression and focus inparticular onmisregulation ofmiRNAswhich leads to several neurodegenerative diseases as well as its therapeutic outcome Recentevidences has shown that miRNAs expression levels are changed in patients with neurodegenerative diseases hence miRNA canbe used as a potential diagnostic biomarker and serve as an effective therapeutic tool in overcoming various neurodegenerativedisease processes

1 Introduction

Genetic and environmental factors can contribute to thedevelopment of neurodegenerative diseases Recent studiesdemonstrate roles for regulatory noncoding RNA molecules(ncRNAs) in normal CNS development and function andin the onset and progression of various neurodegenerativediseases ncRNAs are functional RNA molecules expressedspecifically in the central nervous system that do not encodeproteins They are classified as small ncRNAs comprisingfewer than 400 nucleotides and long ncRNAs comprisingmore than 400 nucleotides Small ncRNAs include ribosomalRNAs (rRNAs) transfer RNAs (tRNAs) small nucleolarRNAs (snRNAs) microRNAs (miRNAs) short small inter-ference RNAs (siRNAs) and piwi-interacting RNAs Longnoncoding RNAs (lncRNAs) include heterogeneous regu-latory molecules such as long intergenic noncoding RNAs(linc RNAs) and natural antisense transcripts (NATs) [1ndash3] ncRNAs play critical roles in neuronal processes suchas transcription of neuronal genes brain morphogenesisneuronal cell specification and formation of memory [3]

2 Biogenesis of MicroRNAs

MicroRNAs (miRNAs) are small RNA molecules (21ndash23nucleotides) involved in the regulation of gene expressionthat bind posttranscriptionally to the 31015840-untranslated regionof target mRNAs and either inhibit translation or degradethe target mRNA [4] A single-stranded RNA miRNA isderived from a 70ndash100-nucleotide hairpin precursor calledpre-miRNA that plays a key role in posttranscriptionalregulation of target gene expression Due to their small sizemiRNAs are potentially a valuable tool for therapy of cancerneurodegenerative and cardiovascular diseases [5 6] ThemiRNAs are transcribed by either RNA polymerase II or IIIin the nucleus to yield primary transcripts (pri-miRNAs) ofdifferent lengths that are processed by the DroshaDGCR8enzyme complex into a sim70 base pair precursor miRNA [7]The precursor miRNAs are transported into the cytoplasmwhere cytoplasmic RNase III enzymes Dicer and Loqua-cious process them into sim22-nucleotide miRNA duplexeswith guide and passenger strandsThe guide strand functionsas amaturemiRNAand is incorporated into anRNA-induced

2 ISRN Neurology

silencing complex (RISC) This complex contains an Arg-onaute (Ago) protein as a primary component that binds tothe target mRNA and degrades the passenger strand MaturemiRNA guides RISC to recognize target sequences locatedin the 31015840UTR of mRNAs which leads to the inhibition oftranslation or degradation of mRNA [6 7]

3 The Role of miRNAs inNeurodegenerative Diseases

Neurodegeneration refers to the death of neurons duringthe normal course of brain development and many studiesdemonstrate the involvement of miRNAs The miRNAs arekey regulators of CNS development involving brain plastic-ity neuronal cell maturation neuronal cell differentiationand synaptogenesis [8 9] Dysregulation of miRNAs leadsto the development of neurodegenerative diseases such asAlzheimerrsquos disease Parkinsonrsquos disease and Huntingtonrsquosdisease [9]

31miRNAs inAlzheimerrsquos Disease Alzheimerrsquos disease (AD)is the most common form of dementia among elderly adultsand causes memory impairment as well as problems withthinking decision-making and behavior AD is character-ized by dysregulated processing of amyloid precursor protein(APP) and the accumulation of amyloid beta (A120573) peptidein brain hippocampus [3] 120573-secretase also known as 120573-siteAPP-cleaving enzyme 1 (BACE 1) cleaves APP to generate A120573peptides [10] Several studies show that increased expressionof APP an integral membrane protein is associated withAD MicroRNAs play an important role in APP regulation[11] Vilardo et al [12] showed that miR-101 negativelyregulates the expression of APP and A120573 accumulation incultured hippocampal neurons thus suggesting an essentialrole for miRNA in the development and progression ofAD [12] Postmortem studies of human brain hippocampusshowed increased levels of BACE1 upregulation of miR-9 miR-125B and miR-125b MIr-146a and downregulationof miR-15a miR-107 and miR-29ab-1 which suggests alink between miRNAs and protease in the progression ofthe disease [3 9] Decrease in the expression of miR-107was observed in patients who exhibit early stages of ADAffymetrix Exon Array microarrays demonstrated a sharpincrease in BACE1 mRNA expression and a decrease in miR-107 expression [13] In addition the miR-29ab-1 cluster isdown-regulated in AD patientrsquos brain while upregulation ofBACE1 is observed which suggests a role for the miR-29ab-1cluster in negative regulation of BACE1 expression that leadsto the accumulation of A120573 peptide [14] Certain patterns ofmiRNA expression in the grey matter of cortex also lead toAD pathogenesis MiR-211 is downregulated in Alzheimerrsquosdisease brain whereas there is an upregulation of miR-424[15]

A murine model of AD showed that there was nocorrelation between BACE1 mRNA and levels of proteinsin the hippocampus of APPSwePS1 mice [16] A study byBoissonneault et al [16] supports the concept that thereis an association between dysfunctional miRNA regulation

of BACE1 expression and AD by further analysis of miR-298 and miR-328 in the hippocampus of APPSwePS1 mice[16] In addition a novel noncoding RNA 17A expressedin human brain is upregulated in cerebral tissues of ADpatients and leads to increased secretion of A120573 peptidesGPR51 alternative splicing and ultimately impaired GABAB function [17] A similar study showed that Neuroblas-toma Differentiation Marker 29 (NDM29) a RNA poly-merase III-dependent noncoding RNA enhances the syn-thesis of amyloid precursor protein eventually resulting inan increase of A120573 secretion that promotes the formationof A120573 peptides as they may occur in Alzheimerrsquos disease[18] NF-120581B signaling regulates miR-146a which is upreg-ulated in AD brains and downregulation of CFH proteinis observed in AD brains which suggests that miR-146atargets CFHprotein a brain inflammatory response repressor[19]

32 miRNAs in Parkinsonrsquos Disease The death of dopaminegenerating cells in the brain substantia nigra and accumula-tion of alpha-synuclein leads to the development of Parkin-sonrsquos disease which is characterized by motor abnormalitiesand sensory mood and cognitive changes [20] SpecificmiRNAs control 120572 synuclein expression A study suggeststhat 120572-synuclein is regulated posttranscriptionally by miR-7 and miR-153 which bind directly to the 31015840-untranslatedregion of 120572 synuclein and suppress its expression In additiondownregulation of 120572 synuclein due to miR-7 and miR-153protects cells from oxidative stress In primary neuronsincreased translation of a luciferase construct that bears 120572synuclein 31015840-untranslated region was reportedly caused byinhibition of micro-RNAs miR-7 and miR-153 [21] Elevatedlevels of fibroblast growth factor 20 (FGF20) genes also lead tooverexpression of 120572 synuclein and eventually to the death ofdopaminergic neurons [13] Furthermore this demonstratesthat binding of miR-433 to a single nucleotide polymorphismin the promoter region of FGF20 disrupts the target sitefor miR-433 which eventually results in overexpression of120572 synuclein [13] Downregulation of miR-7 in the 1-methyl-4-phenyl-1236-tetrahydropyridine-(MPTP-) induced neu-rotoxin PD mouse model suggests that it may protectcells against oxidative stress [20] The most vital gene inParkinsonrsquos disease LRRK2 that functions in the dopaminegenerating cells negatively regulates let-7 and mir-184 whichcauses overexpression of their targets E2F1 andDP eventuallyleads to defects in cell division and cell death [22] Expres-sion of miR-133b is detected in the midbrain dopaminergicneurons but not detected in Parkinsonrsquos disease midbraintissue A negative feedback loop with the transcription factorPITX3 found in midbrain dopamine generating neuronsis formed by the downregulation of mir-133b which is adopaminergic neuron-specific miRNA [4] Downregulationof mir-133b may play a neuroprotective role Furthermore arecent study suggests that overexpression of 120572 synuclein bymiR-433 leads to increased risk of AD [13] Also activationof two neuroprotective genes PTEN-induced putative kinase(PINK1) and Parkinson disease 7 (PARK7) normally involvedin protecting cells from oxidative stress leads to developmentof Parkinsonrsquos disease through PTEN signaling [23]

ISRN Neurology 3

33 miRNAs in Huntingtonrsquos Disease Huntingtonrsquos disease isan autosomal dominant neurodegenerative disease charac-terized by cognitive decline and impaired movement It iscaused by trinucleotide expansion in the gene that encodesa polyglutamine stretch near the N-terminus of huntingtin[24] Multiple studies of miRNAs in mouse and humanbrain have shown miR-22 miR-29c and miR-128 are down-regulated in mice and miR-99lowast miR-29b and miR-124aare down-regulated in humans [25 26] Marti et al showedthat miR-221 and miR-222 are both down-regulated in HDAlso downregulation of miRNAs let-7a let-7c let-7d andlet 7e was observed in HD-FC (frontal cortex) and HD-ST (striatum) whereas there was upregulation of miR-30bmiR-30c and miR-30e in HD-FC and HD-ST [27] ThemiR-30a that is upregulated in HD-FC and HD-ST hasbeen shown to target BDNF which is a REST-modulatedneuronal gene Loss of BDNF leads to loss of medium spinyneurons [28 29] RESTCoREST regulates many miRNAsREST repressor complex regulates miR-9 and miR-9lowast thattarget RESTCoREST expression and are considered to bea part of a double-negative feedback loop [3] Expressionof miR-99lowast miR-124a and miR-132 is regulated by theREST repressor complex including mSin3 REST corepressor1 (COREST) and MeCP2 REST silencing complex and miR-99lowast give rise to a negative feedback loop during the devel-opment of Huntingtonrsquos disease due to the effects of miR-9and miR-9lowast on REST and COREST Several miRNAs suchas miR-99lowast miR-129a miR-132 miR-29b miR-29a miR-330 miR-17 miR-196 miR-222 miR-485 and miR-486 areaffected in HD due to the disrupted miRNA transcriptome[27 30] REST targets miR-9 and miR-124 [27] It was shownthat miR-184 expressed in neurons is upregulated due todepolarization [31] Moreover reports suggest that MiR-34bis elevated in plasma of Huntingtonrsquos disease patients evenbefore the onset of symptoms which implies that miR-34bmay be useful as a potential diagnostic biomarker for HD[32 33]

4 ApplicationsTherapeutic Role

Clearly there is evidence formiRNAs as potential biomarkersto aid in the diagnosis of neurodegenerative diseases [34]For instance RNA interference (RNAi) knocks down thetranslation of certain disease-associated molecules due to thepresence of short hairpin RNAs synthetic double-strandedRNAs and the precursors of artificial miRNAs that areexpressed by viral vectors [35] Similarly several RNA-baseddrugs have been formulated to target various diseases Thesedrugs are synthetic RNAmolecules that mimic a mechanismof action similar to that of endogenous ncRNAsmdashsiRNAsor miRNAs [35] Thus RNA interference technology hasemerged as a potential therapeutic tool for several neurode-generative diseasesWang et al [36] suggest the following twodifferent potential roles of miR-146 (1) as a useful biomarkerin the early diagnosis of AD since it can be detected in humanblood monocytes which aids in easy collection and (2) as atherapeutic tool They also suggest that anti-miR-146a can beused with therapeutic potential to suppress the up-regulatoryeffects of miR-146 [36] Another study conducted to examine

the pattern of A120573 driven neurogenesis in a transgenic mousemodel of AD-Tg-19959 showed that the use of LNA-modifiedsiRNAs led to a marked decrease in the levels of insolubleA120573 peptides and altered the pattern of aggregation of solubleA120573 in the Tg-19959 mouse brain by targeting BACE1 andBACE-ASThis was considered the most useful potential toolfor early diagnosis of AD [37] Cogswell et al [38] identifiedtwo diagnostic biomarkers dysregulation of miRNA in ADpatientsrsquo brains and changes in miRNA specific to AD incerebrospinal fluid [38] Several miRNAs such as miR-133bmiR-7 miR-153 let-7 miR184 and miR-433 may be involvedin the pathophysiology of PD and offer a novel approachfor therapeutic targets In addition the miRNA pathwayis known to play a crucial role in translational regulationin the pathophysiology of PD and hence is consideredone of the most important translation regulation pathways[5]

Harper et al (2005) showednotable signs of improvementin the behavioral abnormalities and neuropathology amongHDpatientswith the use of an adenoassociated virus serotype1 (AAV1) vector that targets themutant humanhtt in the brainof mouse giving rise to U6 promoter-driven shRNA effectorsystem This is also considered as a potential therapeuticapproach in HD [39] In addition noncoding small RNA-based technology plays a pivotal role in the treatment ofHuntingtonrsquos disease [24]

Antisense oligonucleotides (Aos) help to prevent mRNAsbearing mutations by redirecting pre-mRNA splicing Aosthereby emerge as a potential therapeutic tool and act toregulate alternative splicing [40] Overall data suggest thatvarious noncoding RNAs could serve as useful diagnosticbiomarkers and therapeutic targets for neurodegenerativediseases

5 Future Projections

ncRNAs especially miRNAs are known for their roles innormal development and function of the central nervoussystemThey are involved in targeted gene expression and actas key regulators in several neuroprotective mechanisms Itis a well-established fact that dysregulation of miRNAs even-tually leads to the development of various neurodegenerativediseases Alterations in the patterns ofmiRNAexpressionwillprobably serve as diagnostic biomarkers of brain functionand the initiation and progression of neurological disordersand neurodegenerative diseases [41] Further research inmiRNA expression patterns and profiling will result in thediscovery of many more novel biomarkers In-depth study todetermine the functions of long noncoding RNAs in RNA-mediated gene regulation is likely to remain an area of intenseresearch interest [9]

Acknowledgments

This work was supported by the Auburn University Intra-mural Grants Program (AU-IGP) and Alabama AgriculturalExperimental Station HatchMultistate Funding Program (JR Babu)

4 ISRN Neurology

References

[1] I A Qureshi J S Mattick andM F Mehler ldquoLong non-codingRNAs in nervous system function and diseaserdquo Brain Researchvol 1338 pp 20ndash35 2010

[2] J S Mattick ldquoThe central role of RNA in human developmentand cognitionrdquo FEBS Letters vol 585 no 11 pp 1600ndash1616 2011

[3] E Salta and B D Strooper ldquoNon-coding RNAs with essentialroles in neurodegenerative disordersrdquo The Lancet Neurologyvol 11 no 2 pp 189ndash200 2012

[4] J Kim K Inoue J Ishii et al ldquoA microRNA feedback circuitin midbrain dopamine neuronsrdquo Science vol 317 no 5842 pp1220ndash1224 2007

[5] M D Harraz T M Dawson and V L Dawson ldquoMicroRNAsin Parkinsonrsquos diseaserdquo Journal of Chemical Neuroanatomy vol42 no 2 pp 127ndash130 2011

[6] N K Liu and X M Xu ldquoMicroRNA in central nervous systemtrauma and degenerative disordersrdquo Physiological Genomicsvol 43 no 10 pp 571ndash580 2011

[7] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[8] P T Nelson W X Wang and B W Rajeev ldquoMicroRNAs(miRNAs) in neurodegenerative diseasesrdquo Brain Pathology vol18 no 1 pp 130ndash138 2008

[9] S Bian and T Sun ldquoFunctions of noncoding RNAs in neuraldevelopment and neurological diseasesrdquo Molecular Neurobiol-ogy vol 44 no 3 pp 359ndash373 2011

[10] P Provost ldquoMicroRNAs as amolecular basis formental retarda-tion Alzheimerrsquos and prion diseasesrdquo Brain Research vol 1338pp 58ndash66 2010

[11] L Du and A Pertsemlidis ldquoCancer and neurodegenerativedisorders pathogenic convergence through microRNA regula-tionrdquo Journal of Molecular Cell Biology vol 3 no 3 pp 176ndash1802011

[12] E Vilardo C Barbato M Ciotti C Cogoni and F RubertildquoMicroRNA-101 regulates amyloid precursor protein expressionin hippocampal neuronsrdquo The Journal of Biological Chemistryvol 285 no 24 pp 18344ndash18351 2010

[13] GWang J M van derWalt G Mayhew et al ldquoVariation in themiRNA-433 binding site of FGF20 confers risk for parkinsondisease by overexpression of 120572-synucleinrdquo American Journal ofHuman Genetics vol 82 no 2 pp 283ndash289 2008

[14] S S Hebert K Horre L Nicolai et al ldquoLoss of microRNAcluster miR-29ab-1 in sporadic Alzheimerrsquos disease correlateswith increased BACE1beta-secretase expressionrdquo Proceedingsof the National Academy of the Sciences of the United States ofAmerica vol 105 no 17 pp 6415ndash6420 2008

[15] W X Wang Q Huang Y Hu A J Stromberg and P TNelson ldquoPatterns of microRNA expression in normal andearly Alzheimerrsquos disease human temporal cortex white matterversus gray matterrdquo Acta Neuropathologica vol 121 no 2 pp193ndash205 2011

[16] V Boissonneault I Plante S Rivest and P ProvostldquoMicroRNA-298 and microRNA-328 regulate expressionof mouse 120573-amyloid precursor protein-converting enzyme1rdquo The Journal of Biological Chemistry vol 284 no 4 pp1971ndash1981 2009

[17] S Massone I Vassallo G Fiorino et al ldquo17A a novel non-coding RNA regulates GABA B alternative splicing and sig-naling in response to inflammatory stimuli and in AlzheimerdiseaserdquoNeurobiology of Disease vol 41 no 2 pp 308ndash317 2011

[18] S Massone E Ciarlo S Vella et al ldquoNDM29 a RNA poly-merase III-dependent non-coding RNA promotes amyloido-genic processing of APP and amyloid 120573 secretionrdquo Biochimicaet Biophysica Acta vol 1823 no 7 pp 1170ndash1177 2012

[19] W J Lukiw Y Zhao and G C Jian ldquoAn NF-120581B-sensitive microRNA-146a-mediated inflammatory circuit in alzheimer diseaseand in stressed human brain cellsrdquo The Journal of BiologicalChemistry vol 283 no 46 pp 31315ndash31322 2008

[20] E Junn K W Lee S J Byeong T W Chan J Y Im andM M Mouradian ldquoRepression of 120572-synuclein expression andtoxicity by microRNA-7rdquo Proceedings of the National Academyof Sciences of the United States of America vol 106 no 31 pp13052ndash13057 2009

[21] E Doxakis ldquoPost-transcriptional regulation of 120572-synucleinexpression by mir-7 and mir-153rdquo The Journal of BiologicalChemistry vol 285 no 17 pp 12726ndash12734 2010

[22] S Gehrke Y Imai N Sokol and B Lu ldquoPathogenic LRRK2neg-atively regulates microRNA-mediated translational repressionrdquoNature vol 466 no 7306 pp 637ndash641 2010

[23] L G T Morris S Veeriah and T A Chan ldquoGenetic determi-nants at the interface of cancer and neurodegenerative diseaserdquoOncogene vol 29 no 24 pp 3453ndash3464 2010

[24] Y Zhang andRM Friedlander ldquoUsing non-coding small RNAsto develop therapies for Huntingtonrsquos diseaserdquo Gene Therapyvol 18 no 12 pp 1139ndash1149 2011

[25] R Johnson and N J Buckley ldquoGene dysregulation in Hunting-tonrsquos disease REST microRNAs and beyondrdquo NeuromolecularMedicine vol 11 no 3 pp 183ndash199 2009

[26] S T Lee K Chu W S Im et al ldquoAltered microRNA regulationin Huntingtonrsquos disease modelsrdquo Experimental Neurology vol227 no 1 pp 172ndash179 2011

[27] E Marti L Pantano M Banez-Coronel et al ldquoA myriad ofmiRNA variants in control and Huntingtonrsquos disease brainregions detected by massively parallel sequencingrdquo NucleicAcids Research vol 38 no 20 pp 7219ndash7235 2010

[28] C Zuccato A Ciammola D Rigamonti et al ldquoLoss ofhuntingtin-mediated BDNF gene transcription in Huntingtonrsquosdiseaserdquo Science vol 293 no 5529 pp 493ndash498 2001

[29] N Mellios H S Huang A Grigorenko E Rogaev and SAkbarian ldquoA set of differentially expressed miRNAs includingmiR-30a-5p act as post-transcriptional inhibitors of BDNF inprefrontal cortexrdquoHumanMolecular Genetics vol 17 no 19 pp3030ndash3042 2008

[30] R Johnson C Zuccato N D Belyaev D J Guest E Cattaneoand N J Buckley ldquoA microRNA-based gene dysregulationpathway in Huntingtonrsquos diseaserdquo Neurobiology of Disease vol29 no 3 pp 438ndash445 2008

[31] T Nomura M Kimura T Horii et al ldquoMeCP2-dependentrepression of an imprintedmiR-184 released by depolarizationrdquoHuman Molecular Genetics vol 17 no 8 pp 1192ndash1199 2008

[32] C Conaco S Otto J J Han and G Mandel ldquoReciprocalactions of REST and a microRNA promote neuronal identityrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 7 pp 2422ndash2427 2006

[33] A N Packer Y Xing S Q Harper L Jones and B L DavidsonldquoThe bifunctional microRNA miR-9miR-9lowast regulates RESTand CoREST and is downregulated in Huntingtonrsquos diseaserdquoJournal of Neuroscience vol 28 no 53 pp 14341ndash14346 2008

[34] G S Mack ldquoMicroRNA gets down to businessrdquoNature Biotech-nology vol 25 no 6 pp 631ndash638 2007

ISRN Neurology 5

[35] T A Cooper LWan and G Dreyfuss ldquoRNA and diseaserdquo Cellvol 136 no 4 pp 777ndash793 2009

[36] L L Wang Y Huang G Wang and S D Chen ldquoThe potentialrole of microRNA-146 in Alzheimerrsquos disease biomarker ortherapeuticrdquo Medical Hypotheses vol 78 no 3 pp 398ndash4012012

[37] F Modarressi M A Faghihi N S Patel B G SahaganC Wahlestedt and M A Lopez-Toledano ldquoKnockdown ofBACE1-AS Nonprotein-Coding Transcript modulates beta-amyloid related hippocampal neurogenesisrdquo International Jour-nal of Alzheimerrsquos Disease vol 2011 Article ID 929042 11 pages2011

[38] J P Cogswell J Ward I A Taylor et al ldquoIdentification ofmiRNA changes in Alzheimerrsquos disease brain and CSF yieldsputative biomarkers and insights into disease pathwaysrdquo Journalof Alzheimerrsquos Disease vol 14 no 1 pp 27ndash41 2008

[39] S Q Harper P D Staber X He et al ldquoRNA interferenceimproves motor and neuropathological abnormalities in aHuntingtonrsquos disease mouse modelrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 102 no16 pp 5820ndash5825 2005

[40] P Sazani and R Kole ldquoModulation of alternative splicing byantisense oligonucleotidesrdquo Progress in Molecular and Subcellu-lar Biology vol 31 pp 217ndash239 2003

[41] W Feng and Y Feng ldquoMicroRNAs in neural cell developmentand brain diseasesrdquo Science China Life Sciences vol 54 no 12pp 1103ndash1112 2011

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Neurology

silencing complex (RISC) This complex contains an Arg-onaute (Ago) protein as a primary component that binds tothe target mRNA and degrades the passenger strand MaturemiRNA guides RISC to recognize target sequences locatedin the 31015840UTR of mRNAs which leads to the inhibition oftranslation or degradation of mRNA [6 7]

3 The Role of miRNAs inNeurodegenerative Diseases

Neurodegeneration refers to the death of neurons duringthe normal course of brain development and many studiesdemonstrate the involvement of miRNAs The miRNAs arekey regulators of CNS development involving brain plastic-ity neuronal cell maturation neuronal cell differentiationand synaptogenesis [8 9] Dysregulation of miRNAs leadsto the development of neurodegenerative diseases such asAlzheimerrsquos disease Parkinsonrsquos disease and Huntingtonrsquosdisease [9]

31miRNAs inAlzheimerrsquos Disease Alzheimerrsquos disease (AD)is the most common form of dementia among elderly adultsand causes memory impairment as well as problems withthinking decision-making and behavior AD is character-ized by dysregulated processing of amyloid precursor protein(APP) and the accumulation of amyloid beta (A120573) peptidein brain hippocampus [3] 120573-secretase also known as 120573-siteAPP-cleaving enzyme 1 (BACE 1) cleaves APP to generate A120573peptides [10] Several studies show that increased expressionof APP an integral membrane protein is associated withAD MicroRNAs play an important role in APP regulation[11] Vilardo et al [12] showed that miR-101 negativelyregulates the expression of APP and A120573 accumulation incultured hippocampal neurons thus suggesting an essentialrole for miRNA in the development and progression ofAD [12] Postmortem studies of human brain hippocampusshowed increased levels of BACE1 upregulation of miR-9 miR-125B and miR-125b MIr-146a and downregulationof miR-15a miR-107 and miR-29ab-1 which suggests alink between miRNAs and protease in the progression ofthe disease [3 9] Decrease in the expression of miR-107was observed in patients who exhibit early stages of ADAffymetrix Exon Array microarrays demonstrated a sharpincrease in BACE1 mRNA expression and a decrease in miR-107 expression [13] In addition the miR-29ab-1 cluster isdown-regulated in AD patientrsquos brain while upregulation ofBACE1 is observed which suggests a role for the miR-29ab-1cluster in negative regulation of BACE1 expression that leadsto the accumulation of A120573 peptide [14] Certain patterns ofmiRNA expression in the grey matter of cortex also lead toAD pathogenesis MiR-211 is downregulated in Alzheimerrsquosdisease brain whereas there is an upregulation of miR-424[15]

A murine model of AD showed that there was nocorrelation between BACE1 mRNA and levels of proteinsin the hippocampus of APPSwePS1 mice [16] A study byBoissonneault et al [16] supports the concept that thereis an association between dysfunctional miRNA regulation

of BACE1 expression and AD by further analysis of miR-298 and miR-328 in the hippocampus of APPSwePS1 mice[16] In addition a novel noncoding RNA 17A expressedin human brain is upregulated in cerebral tissues of ADpatients and leads to increased secretion of A120573 peptidesGPR51 alternative splicing and ultimately impaired GABAB function [17] A similar study showed that Neuroblas-toma Differentiation Marker 29 (NDM29) a RNA poly-merase III-dependent noncoding RNA enhances the syn-thesis of amyloid precursor protein eventually resulting inan increase of A120573 secretion that promotes the formationof A120573 peptides as they may occur in Alzheimerrsquos disease[18] NF-120581B signaling regulates miR-146a which is upreg-ulated in AD brains and downregulation of CFH proteinis observed in AD brains which suggests that miR-146atargets CFHprotein a brain inflammatory response repressor[19]

32 miRNAs in Parkinsonrsquos Disease The death of dopaminegenerating cells in the brain substantia nigra and accumula-tion of alpha-synuclein leads to the development of Parkin-sonrsquos disease which is characterized by motor abnormalitiesand sensory mood and cognitive changes [20] SpecificmiRNAs control 120572 synuclein expression A study suggeststhat 120572-synuclein is regulated posttranscriptionally by miR-7 and miR-153 which bind directly to the 31015840-untranslatedregion of 120572 synuclein and suppress its expression In additiondownregulation of 120572 synuclein due to miR-7 and miR-153protects cells from oxidative stress In primary neuronsincreased translation of a luciferase construct that bears 120572synuclein 31015840-untranslated region was reportedly caused byinhibition of micro-RNAs miR-7 and miR-153 [21] Elevatedlevels of fibroblast growth factor 20 (FGF20) genes also lead tooverexpression of 120572 synuclein and eventually to the death ofdopaminergic neurons [13] Furthermore this demonstratesthat binding of miR-433 to a single nucleotide polymorphismin the promoter region of FGF20 disrupts the target sitefor miR-433 which eventually results in overexpression of120572 synuclein [13] Downregulation of miR-7 in the 1-methyl-4-phenyl-1236-tetrahydropyridine-(MPTP-) induced neu-rotoxin PD mouse model suggests that it may protectcells against oxidative stress [20] The most vital gene inParkinsonrsquos disease LRRK2 that functions in the dopaminegenerating cells negatively regulates let-7 and mir-184 whichcauses overexpression of their targets E2F1 andDP eventuallyleads to defects in cell division and cell death [22] Expres-sion of miR-133b is detected in the midbrain dopaminergicneurons but not detected in Parkinsonrsquos disease midbraintissue A negative feedback loop with the transcription factorPITX3 found in midbrain dopamine generating neuronsis formed by the downregulation of mir-133b which is adopaminergic neuron-specific miRNA [4] Downregulationof mir-133b may play a neuroprotective role Furthermore arecent study suggests that overexpression of 120572 synuclein bymiR-433 leads to increased risk of AD [13] Also activationof two neuroprotective genes PTEN-induced putative kinase(PINK1) and Parkinson disease 7 (PARK7) normally involvedin protecting cells from oxidative stress leads to developmentof Parkinsonrsquos disease through PTEN signaling [23]

ISRN Neurology 3









Acknowledgments


4 ISRN Neurology

References



































ISRN Neurology 5













of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Neurology 3









Acknowledgments


4 ISRN Neurology

References



































ISRN Neurology 5













of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 ISRN Neurology

References



































ISRN Neurology 5













of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Neurology 5













of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article noncoding rnas in neurodegenerative...

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