One of the current challenges of neurodegenerative disease research is to determine whether pathways relevant in either development or as a function of age contribute to neuron survival and thereby contribute to the pathogenic process in human disease. Using a C. elegans model that recapitulates an early phase of expanded polyglutamine (polyQ) neurotoxicity, we previously reported that increased dosage of sirtuin
sir-2.1/SIRT1 is neuroprotective, and requires the longevity-promoting factor
daf-16/FoxO. Here, we report this neuroprotective effect also requires
bar-1/b-catenin, a downstream effector of canonical Wnt that also acts as a DAF-16/FOXO partner, and
ucp-4, a DAF-16 regulated gene that encodes the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously-proposed mechanism in which the SIR-2.1 and b-catenin pathways converge onto DAF-16 to regulate cell survival. Consistent with these effects in nematodes, survival of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice was enhanced with SIRT1 overexpression. In addition, siRNAs of b-catenin enhanced cell death, and these effects were accompanied by the modulation of neuronal UCP (UCP2, UCP4) expression levels. Finally, we further extend these findings where we identify single nucleotide polymorphism in GSK-3b, a major b-catenin repressor, modifies the age-at-onset of motor symptoms in two well-characterized HD cohorts. Our results suggest that FOXO interactors regulate early stages of expanded polyQ toxicity and lead to GSK-3b modulation of the pathogenic process in HD patients.