Rhes elicits sumoylation of mHtt via a mech- anism independent of its GTPase activity but which does require cysteine at CXXX domains

wild-type Rhes. Biochemical studies revealed a substantial reduction of Rhes-C263S binding to Ubc9 and mHtt (Fig. 4D). Finally, Rhes-induced mHtt sumoylation occurred both in the soluble and membrane fractions (fig. S9). In summary, Rhes binds tomHtt and elicits its sumoylation, which is associated with mHtt disaggregation and cell death. In some animal models overexpression of full-length mHtt augments aggregates in the striatum (20, 21), although, in other models, the overexpression leads to fewer or no aggregates (22, 23). In human HD patients and several animal models, aggregates are not correlated with cell death (5, 20, 24–26). Sumoylated mHtt represses nuclear transcription (8). We observed caspase-3 activation in Rhes-mHtt cells, and mHtt is known to induce cytochrome c release (27). Rhes elicits sumoylation of mHtt via a mechanism independent of its GTPase activity but which does require cysteine at CXXX domains presumably for farnesylation and membrane attachment. Sumoylation of mHtt, RanGAP1, and SP100 occurs in the absence of Rhes but is markedly augmented by Rhes. The three wellstudied SUMO E3 ligases, the PIASy family, Pc2, and RanBP2, do not share obvious sequence homology with each other (28) or with Rhes, the only G protein with demonstrated E3 ligase activity. Dexras1, a close homolog of Rhes, displays the highest levels in the brain, but with nomarked regional differences (29). Dexras1 mediates linking of nitric oxide (NO) signaling by CAPON, a scaffolding protein, which links Dexras1 to neuronal NO synthase (29). NO serves as a guanine nucleotide–exchange factor to activate Dexras1. Dexras1 also mediates neurotoxic iron influx following glutamate–N-methyl-D-aspartate neurotransmission (30). Our discovery that the striatal-selective protein Rhes partners with mHtt to elicit cytotoxicity can account for the striatal pathophysiology of HD. Although Rhes is uniquely enriched in the striatum, it displays detectable cerebral cortical levels with negligible values in the cerebellum (9, 31). Cortical damage presumably elicits dementia; however, the cerebellum is relatively impervious to neurotoxic damage. Because HD can be diagnosed many years before the onset of symptoms, prophylactic therapy could, in principle, prevent or delay the onset of symptoms. Drugs that block the binding of Rhes and mHtt may thus have therapeutic potential.