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 May 18;22(10):5326. doi: 10.3390/ijms22105326.

Abstract

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA 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 transcript 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, 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: 3,4-methylenedioxymethamphetamine (MDMA); Huntington’s disease; L-Dopa-induced dyskinesia (LID); SUMO E3 ligase; autophagy; mTOR; mitophagy; substantia nigra.

Publication types

  • Review

MeSH terms

  • Animals
  • Autophagy
  • Brain / metabolism
  • Brain / pathology
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dopaminergic Neurons / metabolism*
  • GTP-Binding Proteins / deficiency
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Humans
  • Levodopa / metabolism
  • Mice
  • Mice, Knockout
  • Mitophagy
  • Models, Neurological
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Synaptic Transmission

Substances

  • RNA, Messenger
  • Levodopa
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Proteins
  • RASD2 protein, human
  • Rasd2 protein, mouse