Gene co-expression analysis identifies histone deacetylase 5 and 9 expression in midbrain dopamine neurons and as regulators of neurite growth via bone morphogenetic protein signalling

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dc.contributor.author Mazzocchi, Martina
dc.contributor.author Wyatt, Sean L.
dc.contributor.author Mercatelli, Daniela
dc.contributor.author Morari, Michele
dc.contributor.author Morales-Prieto, Noelia
dc.contributor.author Collins, Louise M.
dc.contributor.author Sullivan, Aideen M.
dc.contributor.author O'Keeffe, Gerard W.
dc.date.accessioned 2019-10-14T19:41:41Z
dc.date.available 2019-10-14T19:41:41Z
dc.date.issued 2019-09-13
dc.identifier.citation Mazzocchi, M., Wyatt, S. L., Mercatelli, D., Morari, M., Morales-Prieto, N., Collins, L. M., Sullivan, A. M. and O’Keeffe, G. W. (2019) 'Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling', Frontiers in Cell and Developmental Biology, 7, 191. (14pp.) DOI: 10.3389/fcell.2019.00191 en
dc.identifier.volume 7 en
dc.identifier.startpage 1 en
dc.identifier.endpage 14 en
dc.identifier.issn 2296-634X
dc.identifier.uri http://hdl.handle.net/10468/8746
dc.identifier.doi 10.3389/fcell.2019.00191 en
dc.description.abstract Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP<sup>+</sup>. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Frontiers Media en
dc.relation.uri https://www.frontiersin.org/articles/10.3389/fcell.2019.00191/full
dc.rights ©2019 Mazzocchi, Wyatt, Mercatelli, Morari, Morales-Prieto, Collins, Sullivan and O’Keeffe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ en
dc.subject Parkinson's disease en
dc.subject Alpha- synuclein en
dc.subject Histone deacetylase (HDAC) en
dc.subject Bone morphogenetic protein en
dc.subject Axon en
dc.subject Neurite growth en
dc.subject Degeneration en
dc.subject Survival en
dc.subject HDAC inhibitor (histone deacetylase inhibitor) en
dc.title Gene co-expression analysis identifies histone deacetylase 5 and 9 expression in midbrain dopamine neurons and as regulators of neurite growth via bone morphogenetic protein signalling en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Gerard O Keeffe, Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland. +353-21-490-3000 Email:g.okeeffe@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Irish Research Council en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Frontiers in Cell and Development Biology en
dc.internal.IRISemailaddress g.okeeffe@ucc.ie en
dc.identifier.articleid 191 en
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Career Development Award/15/CDA/3498/IE/Development of GDF5 neurotrophic factor therapy for Parkinson_s disease./ en


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©2019 Mazzocchi, Wyatt, Mercatelli, Morari, Morales-Prieto, Collins, Sullivan and O’Keeffe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Except where otherwise noted, this item's license is described as ©2019 Mazzocchi, Wyatt, Mercatelli, Morari, Morales-Prieto, Collins, Sullivan and O’Keeffe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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