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dc.contributor.authorShulman, Joshua
dc.contributor.authorImboywa, Selina
dc.contributor.authorGiagtzoglou, Nikolaos
dc.contributor.authorPowers, Martin
dc.contributor.authorHu, Yanhui
dc.contributor.authorDevenport, Danelle
dc.contributor.authorChipendo, Portia
dc.contributor.authorChibnik, Lori
dc.contributor.authorDiamond, Allison
dc.contributor.authorPerrimon, Norbert
dc.contributor.authorBrown, Nicholas
dc.contributor.authorDe Jager, Philip L.
dc.contributor.authorFeany, Mel
dc.date.accessioned2019-09-21T09:03:13Z
dc.date.issued2014
dc.identifier.citationShulman, J. M., S. Imboywa, N. Giagtzoglou, M. P. Powers, Y. Hu, D. Devenport, P. Chipendo, et al. 2013. “Functional Screening in Drosophila Identifies Alzheimer’s Disease Susceptibility Genes and Implicates Tau-Mediated Mechanisms.” Human Molecular Genetics 23 (4): 870–77. https://doi.org/10.1093/hmg/ddt478.
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41384485*
dc.description.abstractUsing a Drosophila model of Alzheimers 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 caused by 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.
dc.language.isoen_US
dc.publisherOxford University Press
dash.licenseMETA_ONLY
dc.titleFunctional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalHuman Molecular Genetics
dash.depositing.authorPerrimon, Norbert::4e34fce71a186b488b1846b199007bfb::600
dc.date.available2019-09-21T09:03:13Z
dash.workflow.comments1Science Serial ID 44063
dc.identifier.doi10.1093/hmg/ddt478
dash.source.volume23;4
dash.source.page870


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