Gene co-expression analysis of the human substantia nigra identifies BMP2 as a neurotrophic factor that can promote neurite growth in cells overexpressing wild-type or A53T α-synuclein

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dc.contributor.author Goulding, Susan R.
dc.contributor.author Sullivan, Aideen M.
dc.contributor.author O'Keeffe, Gerard W.
dc.contributor.author Collins, Louise M.
dc.date.accessioned 2019-05-07T12:00:46Z
dc.date.available 2019-05-07T12:00:46Z
dc.date.issued 2019-04-11
dc.identifier.citation Goulding, S. R., Sullivan, A. M., O'Keeffe, G. W. and Collins, L. M. (2019) 'Gene co-expression analysis of the human substantia nigra identifies BMP2 as a neurotrophic factor that can promote neurite growth in cells overexpressing wild-type or A53T α-synuclein', Parkinsonism and Related Disorders. doi: 10.1016/j.parkreldis.2019.04.008 en
dc.identifier.issn 1353-8020
dc.identifier.uri http://hdl.handle.net/10468/7858
dc.identifier.doi 10.1016/j.parkreldis.2019.04.008 en
dc.description.abstract Introduction: α-synuclein-induced degeneration of dopaminergic neurons has been proposed to be central to the early progression of Parkinson's disease. This highlights the need to identify factors that are neuroprotective or neuroregenerative against α-synuclein-induced degeneration. Due to their potent neurotrophic effects on nigrostriatal dopaminergic neurons, we hypothesized that members of the bone morphogenetic protein (BMP) family have potential to protect these cells against α-synuclein. Methods: To identify the most relevant BMP ligands, we used unbiased gene co-expression analysis to identify all BMP family members having a significant positive correlation with five markers of dopaminergic neurons in the human substantia nigra (SN). We then tested the ability of lead BMPs to promote neurite growth in SH-SY5Y cells and in primary cultures of ventral mesencephalon (VM) dopaminergic neurons, treated with either 6-OHDA or MPP+, or overexpressing wild-type or A53T α-synuclein. Results: Only the expression of BMP2 was found to be significantly correlated with multiple dopaminergic markers in the SN. We found that BMP2 treatment promoted neurite growth in SH-SY5Y cells and in dopaminergic neurons. Moreover, BMP2 treatment promoted neurite growth in both SH-SY5Y cells and VM neurons, treated with the neurotoxins 6-OHDA or MPP+. Furthermore, BMP2 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein. Conclusion: These findings are important given that clinical trials of two neurotrophic factors, GDNF and neurturin, have failed to meet their primary endpoints. Our findings are a key first step in rationalising the further study of BMP2 as a potential neurotrophic factor in α-synuclein-based translational models of Parkinson's disease. en
dc.description.sponsorship Cork Institute of Technology (RISAM Scholarship R00094948) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier Ltd. en
dc.relation.uri http://www.sciencedirect.com/science/article/pii/S1353802019302032
dc.rights © 2019, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license. en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Parkinson's en
dc.subject Degeneration en
dc.subject Neurotrophic factor en
dc.subject Axon growth en
dc.subject α-synuclein en
dc.title Gene co-expression analysis of the human substantia nigra identifies BMP2 as a neurotrophic factor that can promote neurite growth in cells overexpressing wild-type or A53T α-synuclein 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.check.info Access to this article is restricted until 12 months after publication by request of the publisher. en
dc.check.date 2020-04-11
dc.date.updated 2019-05-07T11:52:57Z
dc.description.version Accepted Version en
dc.internal.rssid 484333101
dc.contributor.funder Cork Institute of Technology en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Parkinsonism and Related Disorders en
dc.internal.copyrightchecked Yes
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress g.okeeffe@ucc.ie en
dc.internal.bibliocheck In press. Add vol / issue / page range. Amend citation as necessary. 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
dc.identifier.eissn 1873-5126


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© 2019, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license. Except where otherwise noted, this item's license is described as © 2019, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license.
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