Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability
Abstract Parkinson’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 cluste...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00648-8 |
| _version_ | 1797275418554793984 |
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| author | Patrick J. Kearney Yuanxi Zhang Marianna Liang Yanglan Tan Elizabeth Kahuno Tucker L. Conklin Rita R. Fagan Rebecca G. Pavchinskiy Scott A. Shaffer Zhenyu Yue Haley E. Melikian |
| author_facet | Patrick J. Kearney Yuanxi Zhang Marianna Liang Yanglan Tan Elizabeth Kahuno Tucker L. Conklin Rita R. Fagan Rebecca G. Pavchinskiy Scott A. Shaffer Zhenyu Yue Haley E. Melikian |
| author_sort | Patrick J. Kearney |
| collection | DOAJ |
| description | Abstract Parkinson’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. |
| first_indexed | 2024-03-07T15:13:04Z |
| format | Article |
| id | doaj.art-6c37481e4ef04753b7e5db70242f8c05 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-07T15:13:04Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-6c37481e4ef04753b7e5db70242f8c052024-03-05T18:03:13ZengNature Portfolionpj Parkinson's Disease2373-80572024-02-0110111410.1038/s41531-024-00648-8Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viabilityPatrick J. Kearney0Yuanxi Zhang1Marianna Liang2Yanglan Tan3Elizabeth Kahuno4Tucker L. Conklin5Rita R. Fagan6Rebecca G. Pavchinskiy7Scott A. Shaffer8Zhenyu Yue9Haley E. Melikian10Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolDepartment of Neurology and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Neurology and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiMass Spectrometry Facility, Department of Biochemistry and Molecular Biotechnology, UMASS Chan Medical SchoolBrudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolBrudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolBrudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolBrudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolMass Spectrometry Facility, Department of Biochemistry and Molecular Biotechnology, UMASS Chan Medical SchoolDepartment of Neurology and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiBrudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical SchoolAbstract Parkinson’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.https://doi.org/10.1038/s41531-024-00648-8 |
| spellingShingle | Patrick J. Kearney Yuanxi Zhang Marianna Liang Yanglan Tan Elizabeth Kahuno Tucker L. Conklin Rita R. Fagan Rebecca G. Pavchinskiy Scott A. Shaffer Zhenyu Yue Haley E. Melikian Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability npj Parkinson's Disease |
| title | Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability |
| title_full | Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability |
| title_fullStr | Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability |
| title_full_unstemmed | Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability |
| title_short | Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability |
| title_sort | silencing parkinson s risk allele rit2 sex specifically compromises motor function and dopamine neuron viability |
| url | https://doi.org/10.1038/s41531-024-00648-8 |
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