C06 The β-catenin repressor GSK-3β is a modifier of age at onset in Huntington's disease. (16th November 2010)

• Record Type: Journal Article
• Authors: Parker, J A; Tourette, C; Offner, N; Vazquez-Manrique, R; Mukhopadhyay, A; Darbois, A; Menet, S; Dolbeau, G; Schwenke, S; Maison, P; Orth, M; Brice, A; Dürr, A; Bachoud-Lévi, A-C; Tissenbaum, H A; Néri, C
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 81(2010)Supplement 1
• Page Start: A17
• Page End: A18
• Publication Date: 2010-11-16
• Subjects: neuroprotective network -- FoxO -- Huntington's disease -- motor onset -- modifier genes; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp.2010.222588.6
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : 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.