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Author (up) Shulman, J.M.; Imboywa, S.; Giagtzoglou, N.; Powers, M.P.; Hu, Y.; Devenport, D.; Chipendo, P.; Chibnik, L.B.; Diamond, A.; Perrimon, N.; Brown, N.H.; De Jager, P.L.; Feany, M.B.
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  Title Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms Type Journal Article
  Year 2013 Publication Human Molecular Genetics Abbreviated Journal Hum Mol Genet  
  Volume Issue Pages  
  Keywords  
  Abstract Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (p<10-4) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity due to human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.  
  Address Departments of Neurology and Molecular and Human Genetics, Program in Developmental Biology, Baylor College of Medicine, and  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0964-6906 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24067533 Approved no  
  Call Number @ @ Serial 42509  
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