Huntington"s disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in huntingtin. Although HD is inherited, its age of onset shows great variability, suggesting neuronal dysfunction and death in HD is influenced by modifier genes. To study how the neuronal cell may respond to mutant htt, we have developed C. elegans transgenics that overexpress mutant N-terminal htt fused to fluorescent proteins in touch receptor neurons. This model shows neuronal dysfunction without cell death, an effect accompanied by aggregate formation and dystrophy of neuronal processes (Parker et al., PNAS 2001). To study the pathways underlying these transgenic phenotypes, we use a combination of C. elegans mutants, RNAi screens, microarray analysis, and physiological analysis. This effort has led us to identify sirtuin activation as a neuroprotective mechanism against the effects of mutant htt expression, an effect mediated by
daf-16/FOXO, (Parker et al., Nature Genetics 2005). Our findings indicated that modulators of organismal longevity like
sir2 and FOXO may modify early-stage pathogenesis of neurodegenerative diseases, defining a new strategy with therapeutic potential. We will present an update on the progress made with our models in better understanding how mutant htt may be toxic to the neuronal cell and how neuroprotection may be achieved.