title: Integration of β-catenin, sirtuin, and FOXO signaling protects from mutant huntingtin toxicity.
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/β-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 β-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of β-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 β-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of β-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.
authors.affiliation: INSERM, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France.
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vazquez-Manrique
authors.forename: Cendrine
authors.initials: C
authors.lastname: Tourette
authors.forename: Francesca
authors.initials: F
authors.lastname: Farina
authors.forename: Nicolas
authors.initials: N
authors.lastname: Offner
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Orfila
authors.forename: Aurélie
authors.initials: A
authors.lastname: Darbois
authors.forename: Sophie
authors.initials: S
authors.lastname: Menet
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Tissenbaum
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D051858:Forkhead Transcription Factors; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000633:toxicity*; D015398:Signal Transduction / Q000502:physiology*; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D051858:Forkhead Transcription Factors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C115014:bar-1 protein, C elegans; D051176:beta Catenin; C108831:daf-16 protein, C elegans; C507014:SIR-2.1 protein, C elegans; D037761:Sirtuins