Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms
作者： J. M. Shulman , S. Imboywa , N. Giagtzoglou , M. P. Powers , Y. Hu
DOI: 10.1093/HMG/DDT478
关键词:
摘要: 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 87 homologous fly was tested for modulation neurotoxicity caused by Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 enhanced Tau neurotoxicity, and most cases reciprocal activation gene expression suppressed toxicity. Our screen implicates cindr, the ortholog CD2AP AD susceptibility gene, as modulator Tau-mediated mechanisms. Importantly, also identify orthologs FERMT2 CELF1 modifiers, these have been independently validated latest GWAS meta-analysis. Both previously implicated with roles cell adhesion, our additionally identifies homolog integrin adhesion receptors, ITGAM ITGA9, modifier neurotoxicity. results highlight pathways important toxicity demonstrate power organism genetic screens functional follow-up GWAS.
oup.com
core.ac.uk
harvard.edu
oxfordjournals.org
sci-hub.se 参考文章(47)
Richard Dearborn, Qi He, Sam Kunes, Yong Dai, Eph Receptor Tyrosine Kinase-Mediated Formation of a Topographic Map in the Drosophila Visual System The Journal of Neuroscience. ,vol. 22, pp. 1338- 1349 ,(2002) , 10.1523/JNEUROSCI.22-04-01338.2002
Joshua M. Shulman, Kewei Chen, Brendan T. Keenan, Lori B. Chibnik, Adam Fleisher, Pradeep Thiyyagura, Auttawut Roontiva, Cristin McCabe, Nikolaos A. Patsopoulos, Jason J. Corneveaux, Lei Yu, Matthew J. Huentelman, Denis A. Evans, Julie A. Schneider, Eric M. Reiman, Philip L. De Jager, David A. Bennett, Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology JAMA Neurology. ,vol. 70, pp. 1150- 1157 ,(2013) , 10.1001/JAMANEUROL.2013.2815
Joshua M. Shulman, Portia Chipendo, Lori B. Chibnik, Cristin Aubin, Dong Tran, Brendan T. Keenan, Patricia L. Kramer, Julie A. Schneider, David A. Bennett, Mel B. Feany, Philip L. De Jager, Functional Screening of Alzheimer Pathology Genome-wide Association Signals in Drosophila The American Journal of Human Genetics. ,vol. 88, pp. 232- 238 ,(2011) , 10.1016/J.AJHG.2011.01.006
Adam C Naj, Gyungah Jun, Gary W Beecham, Li-San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J Gallins, Joseph D Buxbaum, Gail P Jarvik, Paul K Crane, Eric B Larson, Thomas D Bird, Bradley F Boeve, Neill R Graff-Radford, Philip L De Jager, Denis Evans, Julie A Schneider, Minerva M Carrasquillo, Nilufer Ertekin-Taner, Steven G Younkin, Carlos Cruchaga, John S K Kauwe, Petra Nowotny, Patricia Kramer, John Hardy, Matthew J Huentelman, Amanda J Myers, Michael M Barmada, F Yesim Demirci, Clinton T Baldwin, Robert C Green, Ekaterina Rogaeva, Peter St George-Hyslop, Steven E Arnold, Robert Barber, Thomas Beach, Eileen H Bigio, James D Bowen, Adam Boxer, James R Burke, Nigel J Cairns, Chris S Carlson, Regina M Carney, Steven L Carroll, Helena C Chui, David G Clark, Jason Corneveaux, Carl W Cotman, Jeffrey L Cummings, Charles DeCarli, Steven T DeKosky, Ramon Diaz-Arrastia, Malcolm Dick, Dennis W Dickson, William G Ellis, Kelley M Faber, Kenneth B Fallon, Martin R Farlow, Steven Ferris, Matthew P Frosch, Douglas R Galasko, Mary Ganguli, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Sid Gilman, Bruno Giordani, Jonathan D Glass, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Elizabeth Head, Lawrence S Honig, Christine M Hulette, Bradley T Hyman, Gregory A Jicha, Lee-Way Jin, Nancy Johnson, Jason Karlawish, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Edward H Koo, Neil W Kowall, James J Lah, Allan I Levey, Andrew P Lieberman, Oscar L Lopez, Wendy J Mack, Daniel C Marson, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, Joseph E Parisi, Daniel P Perl, Elaine Peskind, Ronald C Petersen, Wayne W Poon, Joseph F Quinn, Ruchita A Rajbhandary, Murray Raskind, Barry Reisberg, John M Ringman, Erik D Roberson, Roger N Rosenberg, Mary Sano, Lon S Schneider, William Seeley, Michael L Shelanski, Michael A Slifer, Charles D Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Rudolph E Tanzi, John Q Trojanowski, Juan C Troncoso, Vivianna M Van Deerlin, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Jennifer Williamson, Randall L Woltjer, Laura B Cantwell, Beth A Dombroski, Duane Beekly, Kathryn L Lunetta, Eden R Martin, M Ilyas Kamboh, Andrew J Saykin, Eric M Reiman, David A Bennett, John C Morris, Thomas J Montine, Alison M Goate, Deborah Blacker, Debby W Tsuang, Hakon Hakonarson, Walter A Kukull, Tatiana M Foroud, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg, Common variants at MS4A4/MS4A6E , CD2AP , CD33 and EPHA1 are associated with late-onset Alzheimer's disease Nature Genetics. ,vol. 43, pp. 436- 443 ,(2011) , 10.1038/NG.801
Peter McQuilton, Susan E St. Pierre, Jim Thurmond, FlyBase Consortium, None, FlyBase 101 – the basics of navigating FlyBase Nucleic Acids Research. ,vol. 40, pp. 706- 714 ,(2012) , 10.1093/NAR/GKR1030
Jian-Quan Ni, Rui Zhou, Benjamin Czech, Lu-Ping Liu, Laura Holderbaum, Donghui Yang-Zhou, Hye-Seok Shim, Rong Tao, Dominik Handler, Phillip Karpowicz, Richard Binari, Matthew Booker, Julius Brennecke, Lizabeth A Perkins, Gregory J Hannon, Norbert Perrimon, A genome-scale shRNA resource for transgenic RNAi in Drosophila Nature Methods. ,vol. 8, pp. 405- 407 ,(2011) , 10.1038/NMETH.1592
Atsushi Wada, Kagayaki Kato, Makiko F. Uwo, Shigenobu Yonemura, Shigeo Hayashi, Specialized extraembryonic cells connect embryonic and extraembryonic epidermis in response to Dpp during dorsal closure in Drosophila Developmental Biology. ,vol. 301, pp. 340- 349 ,(2007) , 10.1016/J.YDBIO.2006.09.020
Neil X Krueger, David Van Vactor, Hong I Wan, William M Gelbart, Corey S Goodman, Haruo Saito, The Transmembrane Tyrosine Phosphatase DLAR Controls Motor Axon Guidance in Drosophila Cell. ,vol. 84, pp. 611- 622 ,(1996) , 10.1016/S0092-8674(00)81036-3
J.E. Lai-Cheong, M. Parsons, J.A. McGrath, The role of kindlins in cell biology and relevance to human disease The International Journal of Biochemistry & Cell Biology. ,vol. 42, pp. 595- 603 ,(2010) , 10.1016/J.BIOCEL.2009.10.015
Chih-Kang Chiang, Reiko Inagi, Glomerular diseases: genetic causes and future therapeutics Nature Reviews Nephrology. ,vol. 6, pp. 539- 554 ,(2010) , 10.1038/NRNEPH.2010.103