title: The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans.
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.
authors: Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Eleonora
authors: E
authors: Khabirova
authors: Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors: Aileen
authors: A
authors: Moloney
authors: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors: Stefan J
authors: SJ
authors: Marciniak
authors: Department of Psychiatry and Neurology, MRC Centre for Neuropsychiatric Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors: Julie
authors: J
authors: Williams
authors: Department of Medicine, University College London, London, United Kingdom.
authors: David A
authors: DA
authors: Lomas
authors: Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
authors: Stephen G
authors: SG
authors: Oliver
authors: Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
authors: Giorgio
authors: G
authors: Favrin
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; The Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors: David B
authors: DB
authors: Sattelle
authors: Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors: Damian C
authors: DC
authors: Crowther
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology*; D010641:Phenotype; D034622:RNA Interference
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones