Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity

Abstract

Rhes-olving Huntington's Disease? Huntington's disease (HD) is caused by a single dominant mutation of huntingtin (Htt), a protein that occurs in all tissues of the body and that is uniformly distributed throughout the brain. How mutant Htt (mHtt) selectively damages striatal neurons with negligible alterations elsewhere has been a mystery. Subramaniam et al. (p. 1327 ) show that Rhes, a small G protein very highly localized to the striatum, binds mHtt and augments its neurotoxicity. Rhes promotes sumoylation of mHtt, leading to its disaggregation and augmented cytotoxicity. The findings establish how mHtt selectively kills cells in the striatum and suggest that Rhes-Htt binding might provide a therapeutic target.