Huntington's disease is a disorder of the corpus striatum: focus on Rhes (Ras homologue enriched in the striatum).
Despite identification of the gene for huntingtin (Htt) as causal in Huntington's Disease (HD), explication of HD symptoms and selective damage to the corpus striatum has been elusive. The small G protein Rhes Ras homolog enriched in striatum, highly localized to the striatum, binds selectively to mutant Htt (mHtt) and enhances sumoylation of mHtt. Sumoylation disaggregates mHtt and augments its cytotoxicity. Thus, it appears likely that Rhes-mHtt interaction accounts in substantial part for the selective striatal neurotoxicity of HD with associated extrapyramidal symptomatology. Rhes also binds and activates mTOR, enhancing its influence on protein synthesis, and may be the principal determinant of striatal mTOR activation. In HD, sequestration of Rhes by mHtt may decrease its access to mTOR. The attendant loss of protein translational stimulation may explain the pronounced striatal atrophy of HD. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. ssnyder@jhmi.edu
Srinivasa
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Subramaniam
Solomon H
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Snyder
D000818:Animals; D003342:Corpus Striatum / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D004268:DNA-Binding Proteins; C096896:HAP1 protein, human; C073368:HIP1 protein, human; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C486702:RASD2 protein, human; C488189:Rasd2 protein, mouse