title: The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity.
abstract: The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France; Assistance Publique-Hopitaux de Paris (AP-HP), Charles Foix Hospital, Functional Exploration Unit, Ivry-sur-Seine, France.
authors: Cendrine
authors: C
authors: Tourette
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Francesca
authors: F
authors: Farina
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Rafael P
authors: RP
authors: Vazquez-Manrique
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Anne-Marie
authors: AM
authors: Orfila
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Jessica
authors: J
authors: Voisin
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Sonia
authors: S
authors: Hernandez
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Nicolas
authors: N
authors: Offner
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: J Alex
authors: JA
authors: Parker
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Sophie
authors: S
authors: Menet
authors: Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Jinho
authors: J
authors: Kim
authors: University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America.
authors: Jungmok
authors: J
authors: Lyu
authors: University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America.
authors: Si Ho
authors: SH
authors: Choi
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Kerry
authors: K
authors: Cormier
authors: Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Christina K
authors: CK
authors: Edgerly
authors: Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Olivia L
authors: OL
authors: Bordiuk
authors: VA Bedford Geriatric Research Education and Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts, United States of America.
authors: Karen
authors: K
authors: Smith
authors: Pasteur Institute, Cytometry Platform, Paris, France.
authors: Anne
authors: A
authors: Louise
authors: Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
authors: Michael
authors: M
authors: Halford
authors: Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
authors: Steven
authors: S
authors: Stacker
authors: Mines ParisTech, Center for Computational Biology, Fontainebleau, France; Curie Institute, Research Center, Paris, France; INSERM, Unit 900, Paris, France.
authors: Jean-Philippe
authors: JP
authors: Vert
authors: Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Robert J
authors: RJ
authors: Ferrante
authors: University of Southern California Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Los Angeles, California, United States of America.
authors: Wange
authors: W
authors: Lu
authors: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France; Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France; INSERM, Unit 894, Paris, France.
authors: Christian
authors: C
authors: Neri
mesh_terms: D000368:Aged; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D053764:Presenilin-1 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D060490:Receptors, Wnt / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D053764:Presenilin-1; D060490:Receptors, Wnt; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C580804:presenilin 1, mouse; C492691:LIN-18 protein, C elegans; D020794:Receptor Protein-Tyrosine Kinases