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dc.contributor.authorKearney, Patrick J
dc.contributor.authorZhang, Yuanxi
dc.contributor.authorLiang, Marianna
dc.contributor.authorTan, Yanglan
dc.contributor.authorKahuno, Elizabeth
dc.contributor.authorConklin, Tucker L
dc.contributor.authorFagan, Rita R
dc.contributor.authorPavchinskiy, Rebecca G
dc.contributor.authorShaffer, Scott A
dc.contributor.authorYue, Zhenyu
dc.contributor.authorMelikian, Haley E
dc.date.accessioned2024-03-29T14:44:25Z
dc.date.available2024-03-29T14:44:25Z
dc.date.issued2024-02-23
dc.identifier.citationKearney PJ, Zhang Y, Liang M, Tan Y, Kahuno E, Conklin TL, Fagan RR, Pavchinskiy RG, Shaffer SA, Yue Z, Melikian HE. Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability. NPJ Parkinsons Dis. 2024 Feb 23;10(1):41. doi: 10.1038/s41531-024-00648-8. PMID: 38395968; PMCID: PMC10891080.en_US
dc.identifier.issn2373-8057
dc.identifier.doi10.1038/s41531-024-00648-8en_US
dc.identifier.pmid38395968
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53252
dc.description.abstractParkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself impacts DA neuron function and/or viability. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide clear evidence that Rit2 loss is causal for SNc cell death and motor dysfunction, and reveal key sex-specific differences in the response to Rit2 loss.en_US
dc.language.isoenen_US
dc.relation.ispartofNPJ Parkinson's Diseaseen_US
dc.relation.urlhttps://doi.org/10.1038/s41531-024-00648-8en_US
dc.rightsOpen 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/. © The Author(s) 2024en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCellular neuroscienceen_US
dc.subjectNeurodegenerationen_US
dc.titleSilencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viabilityen_US
dc.typeJournal Articleen_US
dc.source.journaltitleNPJ Parkinson's disease
dc.source.volume10
dc.source.issue1
dc.source.beginpage41
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalNPJ Parkinson's disease
refterms.dateFOA2024-03-29T14:44:27Z
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentBrudnick Neuropsychiatric Research Instituteen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentMelikian Lab
dc.contributor.studentPatrick J Kearney
dc.contributor.studentRita Fagan
dc.contributor.studentRebecca G Pavchinskiy
dc.description.thesisprogramNeuroscience


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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/.
© The Author(s) 2024
Except where otherwise noted, this item's license is described as 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/. © The Author(s) 2024