The mechanisms by which mutant huntingtin induces neurodegeneration were investigated using a cellular model that recapitulates features of neurodegeneration seen in Huntington's disease. When transfected into cultured striatal neurons, mutant huntingtin induces neurodegeneration by an apoptotic mechanism. Antiapoptotic compounds or neurotrophic factors protected neurons against mutant huntingtin. Blocking nuclear localization of mutant huntingtin suppressed its ability to form intranuclear inclusions and to induce neurodegeneration. However, the presence of inclusions did not correlate with huntingtin-induced death. The exposure of mutant huntingtin-transfected striatal neurons to conditions that suppress the formation of inclusions resulted in an increase in mutant huntingtin-induced death. These findings suggest that mutant huntingtin acts within the nucleus to induce neurodegeneration. However, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.

Huntingtin (HTT) is now a famous protein because an abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to the devastating neurodegenerative disorder Huntington's disease (HD). The gene encoding huntingtin, HTT, and its dominantly inherited mutation were identified more than 20 years ago. Subsequently, in the hope of finding a cure for HD, there has been intense research aimed at understanding the molecular mechanisms underlying the deleterious effects of the presence of the abnormal polyQ expansion in HTT. Notwithstanding with the value of this approach, evidence has been emerging of a potential role of context and function of the HTT protein in the specificity and severity of the pathogenicity. HTT is ubiquitous both at the tissue and subcellular levels. It interacts with many partners and has long been considered having no clearly defined cellular function. Based on research over the past 20 years, specifically focused on the function of wild-type HTT, we reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients.