Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability

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

doi:10.1038/s41531-024-00648-8

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.

Authors

Patrick J Kearney^{1

2

3}, Yuanxi Zhang⁴, Marianna Liang⁴, Yanglan Tan^{5

6}, Elizabeth Kahuno¹, Tucker L Conklin^{1

7}, Rita R Fagan^{1

2

8}, Rebecca G Pavchinskiy^{1

2}, Scott A Shaffer⁵, Zhenyu Yue⁴, Haley E Melikian^{9

10}

Affiliations

¹ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, MA, USA.
² Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, USA.
³ University of California, San Diego, CA, USA.
⁴ Department of Neurology and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Mass Spectrometry Facility, Department of Biochemistry and Molecular Biotechnology, UMASS Chan Medical School, Worcester, MA, USA.
⁶ DMPK Group, Merck, S. San Francisco, CA, USA.
⁷ Regeneron, Albany, NY, USA.
⁸ University of California, San Francisco, CA, USA.
⁹ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, MA, USA. haley.melikian@umassmed.edu.
¹⁰ Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, USA. haley.melikian@umassmed.edu.

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.

Abstract

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