Human α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing

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dc.contributor.authorMorales‐Prieto, Noeliaen
dc.contributor.authorBevans, Rebekahen
dc.contributor.authorO'Mahony, Adamen
dc.contributor.authorBarron, Aaron en
dc.contributor.authorDoran, Conor Giles en
dc.contributor.authorMcCarthy, Erin en
dc.contributor.authorConcannon, Ruth M.en
dc.contributor.authorGoulding, Susan R.en
dc.contributor.authorMcCarthy, Cathal M.en
dc.contributor.authorCollins, Louise M.en
dc.contributor.authorSullivan, Aideen M.en
dc.contributor.authorO'Keeffe, Gerard W.en
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderCure Parkinson's Trusten
dc.contributor.funderHORIZON EUROPE Marie Sklodowska-Curie Actionsen
dc.date.accessioned2024-05-13T14:24:48Z
dc.date.available2024-05-13T14:24:48Z
dc.date.issued2024-03-26en
dc.description.abstractParkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague–Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.en
dc.description.sponsorshipScience Foundation Ireland (SFI Grant/Award Number: 19/FFP/6666); Cure Parkinson's Trust (Grant/Award Number: CP:GO01)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide14155en
dc.identifier.citationMorales‐Prieto, N., Bevans, R., O’Mahony, A., Barron, A., Giles Doran, C., McCarthy, E., Concannon, R.M., Goulding, S.R., McCarthy, C.M., Collins, L.M., Sullivan, A.M. and O’Keeffe, G.W. (2024) ‘Human α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing’, Aging Cell, e14155. (7 pp). Available at: https://doi.org/10.1111/acel.14155en
dc.identifier.doihttps://doi.org/10.1016/j.bpsgos.2023.100287en
dc.identifier.endpage7en
dc.identifier.issn1474-9718en
dc.identifier.issn1474-9726en
dc.identifier.journaltitleAging Cellen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/15857
dc.language.isoenen
dc.publisherWileyen
dc.relation.ispartofAging Cellen
dc.relation.project890290en
dc.rights© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectParkinson's disease (PD)en
dc.subjectAgingen
dc.subjectαSyn expressionen
dc.subjectDA neuronen
dc.subjectRisken
dc.subjectAgeen
dc.titleHuman α‐synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageingen
dc.typeArticle (peer-reviewed)en
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