Integration of ß-catenin, sirtuin, and FOXO signaling protects from mutant huntingtin toxicity.

Autors de IIS La Fe

• Rafael Vázquez Manrique

  Autor

Autors aliens a IIS La Fe

• Parker JA
• Tourette C
• Farina F
• Offner N
• Mukhopadhyay A
• Orfila AM
• Darbois A
• Menet S
• Tissenbaum HA
• Neri C

Grups d'Investigació

• Biomedicina Molecular, Celular y Genómica

  

  Leader

  José María Millán Salvador

Abstract

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/ß-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 ß-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of ß-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 ß-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of ß-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.