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Article Dans Une Revue Journal of Neuroscience Année : 2012

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

J. Alex Parker
  • Fonction : Auteur
Rafael P. Vazquez-Manrique
  • Fonction : Auteur
Cendrine Tourette
Francesca Farina
Nicolas Offner
  • Fonction : Auteur
Arnab Mukhopadhyay
  • Fonction : Auteur
Anne-Marie Orfila
  • Fonction : Auteur
Aurelie Darbois
  • Fonction : Auteur
Sophie Menet
  • Fonction : Auteur
Heidi A. Tissenbaum
  • Fonction : Auteur
Christian Neri

Résumé

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.

Dates et versions

hal-01545520 , version 1 (22-06-2017)

Identifiants

Citer

J. Alex Parker, Rafael P. Vazquez-Manrique, Cendrine Tourette, Francesca Farina, Nicolas Offner, et al.. Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity. Journal of Neuroscience, 2012, 32 (36), pp.12630-12640. ⟨10.1523/JNEUROSCI.0277-12.2012⟩. ⟨hal-01545520⟩
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