Integration of β-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

• DOI: 10.1523/jneurosci.0277-12.2012
• Publication Date: 2012-09-05T16:38:31Z
• Authors: J. Alex Parker; Rafael P. Vazquez...; Cendrine Tourette; Francesca Farina; Nicolas Offner; Arnab Mukhopadhyay; Anne-Marie Orfila; Aurélie Darbois; Sophie Menet; Heidi A. Tissenbaum; Christian Neri
• Keywords: Sirtuin 1

One of the current challenges neurodegenerative disease research is to determine whether signaling pathways that are essential cellular homeostasis might contribute neuronal survival and modulate pathogenic process in human disease. In Caenorhabditis elegans , sir-2.1 /SIRT1 overexpression protects neurons from early phases expanded polyglutamine (polyQ) toxicity, this protection requires longevity-promoting factor daf-16/ FOXO. Here, we show neuroprotective effect also DAF-16/FOXO partner bar-1 /β-catenin putative DAF-16-regulated gene ucp-4 sole mitochondrial uncoupling protein (UCP) nematodes. These results fit with a previously proposed mechanism which β-catenin FOXO SIRT1 proteins may together regulate expression cell survival. Knockdown enhanced vulnerability death mutant-huntingtin striatal cells derived HdhQ111 knock-in mice. addition, was compensated by accompanied modulation UCP levels, further highlighting cross-talk between mutant polyQ cytoxicity. Taken together, these suggest integration β-catenin, sirtuin huntingtin toxicity.