title: Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia.
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.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Robert G
authors.initials: RG
authors.lastname: Mealer
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.forename: Roxanne
authors.initials: R
authors.lastname: Barrow
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.forename: Richa
authors.initials: R
authors.lastname: Tyagi
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004185:Disability Evaluation; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology*; D007839:Functional Laterality / Q000187:drug effects / Q000235:genetics; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007980:Levodopa / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D009068:Movement / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011869:Radioligand Assay; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D016895:Culture Media, Serum-Free; D007166:Immunosuppressive Agents; D007980:Levodopa; D016627:Oxidopamine; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D020123:Sirolimus