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The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans

Khabirova, Eleonora, Moloney, Aileen, Marciniak, Stefan J., Williams, Julie, Lomas, David A., Oliver, Stephen G., Favrin, Giorgio, Sattelle, David B. and Crowther, Damian C. 2014. The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans. PLoS ONE 9 (7) , e102985. 10.1371/journal.pone.0102985

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Abstract

The human Aβ peptide causes progressive paralysis when expressed in the muscles of the nematode worm, C. elegans. We have exploited this model of Aβ toxicity by carrying out an RNAi screen to identify genes whose reduced expression modifies the severity of this locomotor phenotype. Our initial finding was that none of the human orthologues of these worm genes is identical with the genome-wide significant GWAS genes reported to date (the “white zone”); moreover there was no identity between worm screen hits and the longer list of GWAS genes which included those with borderline levels of significance (the “grey zone”). This indicates that Aβ toxicity should not be considered as equivalent to sporadic AD. To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists. When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance. Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information: Copyright: © 2014 Khabirova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 25 June 2014
Last Modified: 25 Apr 2019 16:27
URI: http://orca.cf.ac.uk/id/eprint/79588

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