[Abstract unavailable

Huntington's disease (HD) is caused by a polyglutamine repeat in the protein huntingtin (Htt) with mutant Htt (mHtt) expressed throughout the body and similarly in all brain regions. Yet, HD neuropathology is largely restricted to the corpus striatum. We report that the small guanine nucleotide-binding protein Rhes, which is localized very selectively to the striatum, binds physiologically to mHtt. Using cultured cells, we found Rhes induces sumoylation of mHtt, which leads to cytotoxicity. Thus, Rhes-mHtt interactions can account for the localized neuropathology of HD.Huntington's disease (HD), a genetically dominant neurodegenerative disorder, reflects expansion of a polyglutamine repeat in the protein huntingtin (Htt) (1). Mutant Htt (mHtt) occurs uniformly throughout the brain and peripheral tissues. Yet, HD is brain-specific with profound abnormal movements related to selective, gross degeneration of the corpus striatum and lesser damage to the cerebral cortex eliciting dementia (2,3). Molecular mechanisms causing mHtt cytotoxicity are unclear. mHtt forms protein aggregates, which may be neuroprotective with soluble mHtt linked to cytotoxicity (4-7). mHtt is sumoylated, which increases the soluble form of mHtt and elicits cytotoxicity and neurotoxicity in a Drosophila model of HD (8).Rhes (Ras homolog enriched in striatum) is a small guanine nucleotide-binding protein (G protein) very selectively localized to the striatum (9). To determine whether Rhes binds to Htt, we overexpressed Rhes in HEK293 cells where it bound to both wild-type (wt) Htt and mHtt (Fig. 1A) (10). In conditionally immortalized Htt knock-in striatal neuronal cells (11), which lack endogenous Rhes ( fig. S1C), overexpressed Rhes bound robustly to endogenous mHtt (Fig. 1B). In HD transgenic mice (12), endogenous striatal mHtt coprecipitated with Rhes (Fig. 1C). In the presence of purified Rhes and Htt, Rhes bound much more to mHtt than wtHtt protein ( fig. S1A). Rhes did not bind to ataxin ( fig. S1B), a polyglutamine-repeat protein involved in another neurodegenerative disorder, spinocerebellar ataxia.To ascertain whether Rhes influences mHtt cytotoxicity, we used several cell lines. In HEK293 cells, overexpression of mHtt or Rhes alone did not decrease cell survival. However, overexpression of Rhes together with mHtt reduced cell survival by 50%, whereas survival was normal in cells containing wtHtt and Rhes (Fig. 1D). We confirmed that survival of a striatal cell line with mHtt is the same as that in cells with wtHtt (13) (Fig. 1E). Overexpression of Rhes in mHtt knock-in striatal cells (STHdh Q111/Q111 ) (14) reduced cell survival by 60%, whereas over-expression of Rhes in wtHtt knock-in striatal cells (STHdh Q7/Q7 ) had no effect (Fig. 1E). Rhes's influences on striatal cell survival were concentration-dependent ( fig. S2A).

Extracellular signal‐regulated kinase (ERK) is a versatile protein kinase that regulates many cellular functions. Growing evidence suggests that ERK1/2 plays a crucial role in promoting cell death in a variety of neuronal systems, including neurodegenerative diseases. It is believed that the magnitude and the duration of ERK1/2 activity determine its cellular function. In this review, we summarize recent evidence for a role of ERK1/2 in neuronal death. Furthermore, we discuss the mechanisms involved in ERK1/2 mediating neuronal death.