Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia

Nat Neurosci. 2011 Dec 18;15(2):191-3. doi: 10.1038/nn.2994.

Abstract

L-DOPA-induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes(-/-) mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adrenergic Agents / toxicity
  • Animals
  • Antiparkinson Agents / adverse effects
  • Cell Line, Transformed
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Culture Media, Serum-Free / pharmacology
  • Disability Evaluation
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / etiology
  • Dyskinesia, Drug-Induced / pathology*
  • Functional Laterality / drug effects
  • Functional Laterality / genetics
  • GTP-Binding Proteins / deficiency
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Levodopa / adverse effects
  • Mice
  • Mice, Knockout
  • Movement / drug effects
  • Mutation / genetics
  • Neurons / metabolism
  • Neurotoxicity Syndromes / drug therapy
  • Neurotoxicity Syndromes / etiology
  • Oxidopamine / toxicity
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Radioligand Assay
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Adrenergic Agents
  • Antiparkinson Agents
  • Culture Media, Serum-Free
  • Immunosuppressive Agents
  • Levodopa
  • Oxidopamine
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases
  • GTP-Binding Proteins
  • Rasd2 protein, mouse
  • Sirolimus