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Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.

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 is causative for PD or PD-like symptoms. 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 the first evidence that Rit2 loss is causal for SNc cell death and a PD-like phenotype, and reveal key sex-specific differences in the response to Rit2 loss.

SUBMITTER: Kearney PJ

PROVIDER: S-EPMC10168302 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.

Kearney Patrick J PJ Zhang Yuanxi Y Tan Yanglan Y Kahuno Elizabeth E Conklin Tucker L TL Fagan Rita R RR Pavchinskiy Rebecca G RG Shafer Scott A SA Yue Zhenyu Z Melikian Haley E HE

bioRxiv : the preprint server for biology 20231113

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 is causative for PD or PD-like symptoms. Here we report that condition ...[more]

PMID: 37162843

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Project description:The association between idiopathic Parkinson's disease, a paradigmatic dopamine-deficiency syndrome, and problems in the estimation of time has been studied experimentally for decades. I review that literature, which raises a question about whether and if dopamine deficiency relates not only to the motor slowness that is an objective and cardinal parkinsonian sign, but also to a compromised neural substrate for time perception. Why does a clinically (motorically) significant deficiency in dopamine play a role in the subjective perception of time's passage? After a discussion of a classical conception of basal ganglionic control of movement under the influence of dopamine, I describe recent work in healthy mice using optogenetics; the methodology visualizes dopaminergic neuronal firing in very short time intervals, then allows for correlation with motor behaviors in trained tasks. Moment-to-moment neuronal activity is both highly dynamic and variable, as assessed by photometry of genetically defined dopaminergic neurons. I use those animal data as context to review a large experimental experience in humans, spanning decades, that has examined subjective time perception mainly in Parkinson's disease, but also in other movement disorders. Although the human data are mixed in their findings, I argue that loss of dynamic variability in dopaminergic neuronal activity over very short intervals may be a fundamental sensory aspect in the pathophysiology of parkinsonism. An important implication is that therapeutic response in Parkinson's disease needs to be understood in terms of short-term alterations in dynamic neuronal firing, as has already been examined in novel ways-for example, in the study of real-time changes in neuronal network oscillations across very short time intervals. A finer analysis of a treatment's network effects might aid in any effort to augment clinical response to either medications or functional neurosurgical interventions in Parkinson's disease.

Dataset Information

Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.

Publications

Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.

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