Inhibition of miR-181a promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s disease

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dc.contributor.authorHegarty, Shane V.
dc.contributor.authorSullivan, Aideen M.
dc.contributor.authorO'Keeffe, Gerard W.
dc.contributor.funderNational University of Ireland
dc.contributor.funderIrish Research Council
dc.contributor.funderScience Foundation Ireland
dc.date.accessioned2018-02-20T13:24:13Z
dc.date.available2018-02-20T13:24:13Z
dc.date.issued2018
dc.description.abstractParkinson’s disease (PD) is the second most common neurodegenerative disease, and is characterized by the progressive degeneration of nigrostriatal dopaminergic (DA) neurons. Current PD treatments are symptomatic, wear off over time and do not protect against DA neuronal loss. Finding a way to re-grow midbrain DA (mDA) neurons is a promising disease-modifying therapeutic strategy for PD. However, reliable biomarkers are required to allow such growth-promoting approaches to be applied early in the disease progression. miR-181a has been shown to be dysregulated in PD patients, and has been identified as a potential biomarker for PD. Despite studies demonstrating the enrichment of miR-181a in the brain, specifically in neurites of postmitotic neurons, the role of miR-181a in mDA neurons remains unknown. Herein, we used cell culture models of human mDA neurons to investigate a potential role for miR-181a in mDA neurons. We used a bioninformatics analysis to identify that miR-181a targets components of the bone morphogenetic protein (BMP) signalling pathway, including the transcription factors Smad1 and Smad5, which we find are expressed by rat mDA neurons and are required for BMP-induced neurite growth. We also found that inhibition of neuronal miR-181a, resulted in increased Smad signalling, and induced neurite growth in SH-SY5Y cells. Finally, using embryonic rat cultures, we demonstrated that miR-181a inhibition induces ventral midbrain (VM) and cortical neuronal growth. These data describe a new role for miR-181a in mDA neurons, and provide proof of principle that miR-181a dysresgulation in PD may alter the activation state of signalling pathways important for neuronal growth in neurons affected in PD.en
dc.description.sponsorshipIrish Research Council (R15897); National University of Ireland (R16189)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleidNS20170181
dc.identifier.citationHegarty, Shane V., Sullivan, Aideen M. and O’Keeffe, Gerard W. (2018) 'Inhibition of miR-181a promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s disease', Neuronal Signaling, 2(1), NS20170181 (12pp). doi: 10.1042/NS20170181en
dc.identifier.doi10.1042/NS20170181
dc.identifier.endpage12
dc.identifier.issn2059-6553
dc.identifier.issued1
dc.identifier.journaltitleNeuronal Signalingen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/5512
dc.identifier.volume2
dc.language.isoenen
dc.publisherPortland Pressen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Career Development Award/15/CDA/3498/IE/Development of GDF5 neurotrophic factor therapy for Parkinson_s disease./
dc.relation.urihttp://www.neuronalsignaling.org/content/2/1/NS20170181
dc.rights©2018, the Author(s) This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAxonen
dc.subjectDopaminemicroen
dc.subjectRNAen
dc.titleInhibition of miR-181a promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s diseaseen
dc.typeArticle (peer-reviewed)en
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