Gene co-expression analysis of the human substantia nigra identifies ZNHIT1 as an SNCA co-expressed gene that protects against α-synuclein-induced impairments in neurite growth and mitochondrial dysfunction in SH-SY5Y cells

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dc.contributor.authorMcCarthy, Erinen
dc.contributor.authorBarron, Aaronen
dc.contributor.authorMorales-Prieto, Noeliaen
dc.contributor.authorMazzocchi, Martinaen
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.funderIrish Research Councilen
dc.contributor.funderHORIZON EUROPE Marie Sklodowska-Curie Actionsen
dc.date.accessioned2024-05-14T15:54:43Z
dc.date.available2024-05-14T15:54:43Z
dc.date.issued2022-02-17en
dc.description.abstractParkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.en
dc.description.sponsorshipScience Foundation Ireland (SFI grant number 19/FFP/6666); Irish Research Council (GOIPG-2018–2795); Marie Skłodowska-Curie Fellowship programme (grant number MSCA-IF-2019 890290)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMcCarthy, E., Barron, A., Morales-Prieto, N., Mazzocchi, M., McCarthy, C.M., Collins, L.M., Sullivan, A.M. and O’Keeffe, G.W. (2022) ‘Gene co-expression analysis of the human substantia nigra identifies znhit1 as an snca co-expressed gene that protects against α-synuclein-induced impairments in neurite growth and mitochondrial dysfunction in sh-sy5y cells’, Molecular Neurobiology, 59(5), pp. 2745–2757. Available at: https://doi.org/10.1007/s12035-022-02768-9.en
dc.identifier.doihttps://doi.org/10.1007/s12035-022-02768-9en
dc.identifier.endpage2757en
dc.identifier.issn0893-7648en
dc.identifier.issn1559-1182en
dc.identifier.issued5en
dc.identifier.journaltitleMolecular Neurobiologyen
dc.identifier.startpage2745en
dc.identifier.urihttps://hdl.handle.net/10468/15866
dc.identifier.volume59en
dc.language.isoenen
dc.publisherSpringeren
dc.relation.ispartofMolecular Neurobiologyen
dc.rights© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectParkinson’s diseaseen
dc.subjectα-Synucleinen
dc.subjectSNCAen
dc.subjectZNHIT1en
dc.subjectDopamineen
dc.subjectDopaminergicen
dc.subjectSubstantia nigraen
dc.subjectHistone deacetylaseen
dc.subjectAxon degenerationen
dc.subjectHistone acetylationen
dc.titleGene co-expression analysis of the human substantia nigra identifies ZNHIT1 as an SNCA co-expressed gene that protects against α-synuclein-induced impairments in neurite growth and mitochondrial dysfunction in SH-SY5Y cellsen
dc.typeArticle (peer-reviewed)en
oaire.citation.issue5en
oaire.citation.volume59en
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