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dc.contributor.authorZharikov, Alevtina D.
dc.contributor.authorCannon, Jason R.
dc.contributor.authorTapias, Victor
dc.contributor.authorBai, Qing
dc.contributor.authorHorowitz, Max P.
dc.contributor.authorShah, Vipul
dc.contributor.authorEl Ayadi, Amina
dc.contributor.authorHastings, Teresa G.
dc.contributor.authorGreenamyre, J. Timothy
dc.contributor.authorBurton, Edward A.
dc.date.accessioned2024-01-02T00:34:43Z
dc.date.available2024-01-02T00:34:43Z
dc.date.issued2015
dc.identifier.citationJournal of Clinical Investigation, Julio 2015, vol. 125, n. 7. p. 2721-2735es
dc.identifier.issn0021-9738es
dc.identifier.urihttps://uvadoc.uva.es/handle/10324/63883
dc.descriptionProducción Científicaes
dc.description.abstractMultiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson's disease (PD). Occupational exposure to the mitochondrial complex I inhibitor rotenone increases PD risk; rotenone-exposed rats show systemic mitochondrial defects but develop specific neuropathology, including α-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-synuclein in the adult rat substantia nigra by adeno-associated virus-mediated delivery of a short hairpin RNA (shRNA) targeting the endogenous rat Snca transcript. Knockdown of α-synuclein by ~35% did not affect motor function or cause degeneration of nigral dopaminergic neurons in control rats. However, in rotenone-exposed rats, progressive motor deficits were substantially attenuated contralateral to α-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synuclein knockdown. These data show that α-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-synuclein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing α-synuclein expression modulate cellular susceptibility to environmental exposures in PD patients. shRNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in PD.es
dc.format.mimetypeapplication/pdfes
dc.language.isoenges
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleshRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease modeles
dc.typeinfo:eu-repo/semantics/articlees
dc.identifier.doi10.1172/JCI64502es
dc.identifier.publicationfirstpage2721es
dc.identifier.publicationissue7es
dc.identifier.publicationlastpage2735es
dc.identifier.publicationtitleJournal of Clinical Investigationes
dc.identifier.publicationvolume125es
dc.peerreviewedSIes
dc.rightsAtribución 4.0 Internacional
dc.type.hasVersioninfo:eu-repo/semantics/draftes


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