Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms.
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 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.
Department of Neurology and.
Joshua M
JM
Shulman
Selina
S
Imboywa
Nikolaos
N
Giagtzoglou
Martin P
MP
Powers
Yanhui
Y
Hu
Danelle
D
Devenport
Portia
P
Chipendo
Lori B
LB
Chibnik
Allison
A
Diamond
Norbert
N
Perrimon
Nicholas H
NH
Brown
Philip L
PL
De Jager
Mel B
MB
Feany
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D039481:CD11b Antigen / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016023:Integrins / Q000235:genetics; D034622:RNA Interference; D016875:tau Proteins / Q000235:genetics*
D039481:CD11b Antigen; D029721:Drosophila Proteins; C541973:ITGA9 protein, human; C509295:ITGAM protein, human; D016023:Integrins; D016875:tau Proteins