Portal de investigación
The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Tourette C
- Farina F
- Orfila AM
- Voisin J
- Hernandez S
- Offner N
- Parker JA
- Menet S
- Kim J
- Lyu J
- Choi SH
- Cormier K
- Edgerly CK
- Bordiuk OL
- Smith K
- Louise A
- Halford M
- Stacker S
- Vert JP
- Ferrante RJ
- Lu W
- Neri C
Grupos
Abstract
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including gamma-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 beta-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished beta-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 gamma-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.
Datos de la publicación
- ISSN/ISSNe:
- 1545-7885, 1545-7885
- Tipo:
- Article
- Páginas:
- -
PLOS BIOLOGY PUBLIC LIBRARY SCIENCE
Citas Recibidas en Web of Science: 38
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Filiaciones
Proyectos asociados
MOLECULAR MECHANISMS OF PROTEIN AGGREGATION IN VITRO AND IN VIVO MODELS OF HUNTINGTON DISEASE
Investigador Principal: RAFAEL VÁZQUEZ MANRIQUE
CP11/00090 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2012
MECHAGGRENAMICS. MECHANISMS OF CELL DYSFUNCTION BY AGGREGATION DYNAMICS OF POLYQ-CONTAINING PROTEINS
Investigador Principal: RAFAEL VÁZQUEZ MANRIQUE
322034_MARIE_CURIE_VAZQUEZ_FP7-PEOPLE-2012-CIG . COMISION EUROPEA; ASOCIACION VALENCIANA DE ENFERMEDAD HUNTINGTON . 2012
COMPREHENSIVE, INTEGRATIVE AND GENOMIC APPROACH TO THE UNDERSTANDING AND TREATMENT OF CANCER AND LEUKEMIA.
Investigador Principal: MIGUEL ÁNGEL SANZ ALONSO
PIE13/00046 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2014
Cita
Tourette C,Farina F,Vazquez RP,Orfila AM,Voisin J,Hernandez S,Offner N,Parker JA,Menet S,Kim J,Lyu J,Choi SH,Cormier K,Edgerly CK,Bordiuk OL,Smith K,Louise A,Halford M,Stacker S,Vert JP,Ferrante RJ,Lu W,Neri C. The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity. PLoS. Biol. 2014. 12. (6):e1001895. IF:9,343. (1).