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

Author:

Kearney Patrick J.ORCID,Zhang Yuanxi,Liang MariannaORCID,Tan Yanglan,Kahuno ElizabethORCID,Conklin Tucker L.,Fagan Rita R.ORCID,Pavchinskiy Rebecca G.,Shaffer Scott A.ORCID,Yue ZhenyuORCID,Melikian Haley E.ORCID

Abstract

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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

Parkinson’s Disease Foundation

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

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