Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons Degeneration: Link to Parkison’s Disease

Marcello Serra
,
Annalisa Pinna
ORCID logo ,
Giulia Costa
,
Alessandro Usiello
,
Massimo Pasqualetti
ORCID logo ,
Luigi Avallone
,
Micaela Morelli
,
Francesco Napolitano
* ORCID logo
Version 1 : Received: 13 April 2021 / Approved: 14 April 2021 / Online: 14 April 2021 (13:41:05 CEST)

A peer-reviewed article of this Preprint also exists.

Serra, M.; Pinna, A.; Costa, G.; Usiello, A.; Pasqualetti, M.; Avallone, L.; Morelli, M.; Napolitano, F. Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons’ Degeneration: Link to Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 5326. Serra, M.; Pinna, A.; Costa, G.; Usiello, A.; Pasqualetti, M.; Avallone, L.; Morelli, M.; Napolitano, F. Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons’ Degeneration: Link to Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 5326.

Abstract

Rhes is one of the most interesting proteins regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. It is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, several data showed that lack of Rhes enhanced cocaine and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

Keywords

Substantia nigra; mTOR; SUMO E3 ligase; Huntington’s disease; 3,4-methylenedioxymethamphetamine (MDMA); autophagy; L-Dopa-induced dyskinesia (LID); mitophagy

Subject

Social Sciences, Psychology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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