title: Reducing canonical Wingless/Wnt signaling pathway confers protection against mutant Huntingtin toxicity in Drosophila.
abstract: Huntington's disease (HD) is a genetic neurodegenerative disease characterized by movement disorders, cognitive decline and neuropsychiatric symptoms. HD is caused by expanded CAG tract within the coding region of Huntingtin protein. Despite major insights into the molecular mechanisms leading to HD, no effective cure is yet available. Mutant Huntingtin (mHtt) has been reported to alter the stability and levels of β-Catenin, a key molecule in cell adhesion and signal transduction in Wingless (Wg)/Wnt pathway. However it remains to establish whether manipulation of Wg/Wnt signaling can impact HD pathology. We here investigated the phenotypic interactions between mHtt and Wg/Wnt signaling by using the power of Drosophila genetics. We provide compelling evidence that reducing Armadillo/β-Catenin levels confers protection and that this beneficial effect is correlated with the inactivation of the canonical Wg/Wnt signaling pathway. Knockdowns of Wnt ligands or of the downstream transcription factor Pangolin/TCF both ameliorate the survival of HD flies. Similarly, overexpression of one Armadillo/β-Catenin destruction complex component (Axin, APC2 or Shaggy/GSK-3β) increases the lifespan of HD flies. Loss of functional Armadillo/β-Catenin not only abolishes neuronal intrinsic but also glia-induced alterations in HD flies. Our findings highlight that restoring canonical Wg/Wnt signaling may be of therapeutic value.
authors.affiliation: Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CNRS UMR 7286, Aix-Marseille Université, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Dupont
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Besson
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devaux
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Liévens
mesh_terms: D000818:Animals; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D055785:Gene Knockdown Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008124:Locomotion / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000633:toxicity*; D009154:Mutation / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D051155:Wnt1 Protein; C074622:wg protein, Drosophila