Genes and gene networks at the interface between longevity/survival and neuroprotection are currently the subject of intense research. Recent reports based on the use of simple model systems have emphasized a role for these genes in protection against the effects of proteins and polypeptides associated to neurodegenerative diseases. We will present a short overview of recent data in the field. We will also present our most recent data on the study of longevity modulators in simple models of Huntingtons disease (HD) pathogenesis. HD is a neurodegenerative disease caused by expanded polyglutamines (polyQs) in huntingtin (htt). Although HD is inherited, its age-at-onset shows a significant level of variability not fully explained by expanded htt alleles, suggesting a role for modifier genes. We hypothesized HD modifier genes may belong to longevity pathways that modulate the neuronal cell response to mutant htt. To study how the neuronal cell may respond to mutant htt, we use translational research primarily based on the genetic manipulation of C. elegans transgenics at the neuronal cell level and biological assays in cellular and mouse models of HD. We found sirtuin activation is a neuroprotective mechanism against the effects of mutant htt, an effect mediated by
daf-16/FOXO (Parker et al., Nature Genetics 2005), providing the first direct evidence for longevity modulators like Sir2 and FOXO to modify the neurotoxic properties of neurodegenerative disease-associated proteins like mutant htt, and defining a new strategy with therapeutic potential. DAF-16/FOXO has numerous upstream modulators and downstream targets, not all of which are likely to be important to neuronal protection. Using RNAi, we identified a subset of
daf-16 targets that modify the neuronal dysfunction induced by mutant polyQs. We are extending this approach to include the microarray analysis of gene expression profiles in cell-sorted polyQ neurons from C. elegans transgenics. Data integration and classification using gene networks emphasize gene classes, pathways and biological processes that are conserved in humans and may be essential to neuronal cell activity and survival in HD, providing new information to best understand the mechanisms underlying the disease pathogenesis and residual age-at-onset. Drug discovery aspects will also be commented.