Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form
D-Scholarship @ Pitt Banner and Links to Homepage

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

Tourette, C and Farina, F and Vazquez-Manrique, RP and Orfila, AM and Voisin, J and Hernandez, S and Offner, N and Parker, JA and Menet, S and Kim, J and Lyu, J and Choi, SH and Cormier, K and Edgerly, CK and Bordiuk, OL and Smith, K and Louise, A and Halford, M and Stacker, S and Vert, JP and Ferrante, RJ and Lu, W and Neri, C (2014) The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity. PLoS Biology, 12 (6). ISSN 1544-9173

[img]
Preview
 PDF
Published Version
Available under License : See the attached license file.
Download (3MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.
Download (1kB)

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. © 2014 Tourette et al.

Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tourette, C
Farina, F
Vazquez-Manrique, RP
Orfila, AM
Voisin, J
Hernandez, S
Offner, N
Parker, JA
Menet, S
Kim, Jjinhokim@pitt.eduJINHOKIM
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
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorBellen, Hugo J .UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: PLoS Biology
Volume: 12
Number: 6
DOI or Unique Handle: 10.1371/journal.pbio.1001895
Schools and Programs: School of Medicine > Neurological Surgery
Refereed: Yes
ISSN: 1544-9173
Date Deposited: 01 Jul 2014 17:45
Last Modified: 27 Apr 2019 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/22176

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com

Actions (login required)

View Item View Item