Background The FOXO longevity pathway and β-catenin pathway are major signalling systems that may regulate cell survival. Whether GSK3/β-catenin may interact with longevity signalling to regulate diseased neuron survival and whether this may translate into the modification of human neurodegenerative disease remain unknown.
Aims We aimed to test the role of FOXO neighbours such as β-catenin on the effects of expanded polyQs/mutant huntingtin.
Methods We used complementary approaches based on a C elegans model of neuronal dysfunction induced by expanded polyQ expression, a cellular model of HD pathogenesis based on full length huntingtin expression and genotype analysis using DNA samples from HD patients.
Results In C elegans, we observed that neuroprotection by the sirtuin sir-2.1 requires the DAF-16/FOXO partner BAR-1/β-catenin and the DAF-16 target ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. In mutant htt striatal cells from HdhQ111 knock-in mice, β-catenin, FOXO3a, SIRT1 and UCP2 promote cell survival, with a cooperation of β-catenin and SIRT1. In Huntington's disease (HD) patients, a single nucleotide polymorphism in GSK-3β, a major repressor of β-catenin activity, modulates the age at onset of motor symptoms as observed in the French and European cohorts. In these cohorts, GSK-3β may also act in synergy with TCERG1 (also named CA150). TCERG1 is an evolutionary conserved gene known as a neuroprotective factor in models of HD and daf-16/FOXO interactor in nematodes, and is confirmed to modify HD onset age.
Conclusion These data reveal a role for β-catenin on HD neuron survival and they identify GSK-3β as a modifier of age at onset of motor symptoms in HD.
- neuroprotective network
- Huntington's disease
- motor onset
- modifier genes
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