Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity
Authors
Parker, J. AlexVazquez-Manrique, Rafael P.
Tourette, Cendrine
Farina, Francesca
Offner, Nicolas
Mukhopadhyay, Arnab
Orfila, Anne-Marie
Darbois, Aurelie
Menet, Sophie
Tissenbaum, Heidi A.
Neri, Christian
Document Type
Journal ArticlePublication Date
2012-09-05Keywords
Nerve Tissue ProteinsNeurons
Nerve Degeneration
beta Catenin
Sirtuin 1
Forkhead Transcription Factors
Genetics and Genomics
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.Source
J Neurosci. 2012 Sep 5;32(36):12630-40. Link to article on publisher's site
DOI
10.1523/JNEUROSCI.0277-12.2012Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43997PubMed ID
22956852Related Resources
Link to Article in PubMedRights
This article is freely available online through the Journal of Neuroscience Open Choice option.
ae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.0277-12.2012