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PLoS Biol. 2014 Jun 24;12(6):e1001895. doi: 10.1371/journal.pbio.1001895. eCollection 2014 Jun.

The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity.

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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.
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.
Neurological Surgery Department, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
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.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
VA Bedford Geriatric Research Education and Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts, United States of America.
Pasteur Institute, Cytometry Platform, Paris, France.
Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
Mines ParisTech, Center for Computational Biology, Fontainebleau, France; Curie Institute, Research Center, Paris, France; INSERM, Unit 900, Paris, France.


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.

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Conflict of interest statement

The authors have declared that no competing interests exist. Dr. Robert Ferrante is listed as an author of our paper, but at the time of acceptance was not reachable or able to confirm details of his author contributions to the manuscript. The corresponding author, Christian Neri, has therefore supplied the information regarding his contribution to the manuscript and his competing interests and it is correct to the best of Christian Neri's knowledge.

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