Department of Neurology and.
Hum Mol Genet. 2014 Feb 15;23(4):870-7. doi: 10.1093/hmg/ddt478. Epub 2013 Sep 25.
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.
利用阿尔茨海默病（AD）的果蝇模型，我们根据已发表的人类全基因组关联研究（GWAS）中与 AD 相关的基因组位点（P < 10(-4))，系统地评估了 67 个候选基因。对 87 个同源果蝇基因进行遗传操作，以测试其对人 Tau 引起的神经毒性的调节作用，Tau 在 AD 中形成神经纤维缠结病理学。针对 9 个基因的 RNA 干扰（RNAi）增强了 Tau 的神经毒性，并且在大多数情况下，基因表达的反向激活抑制了 Tau 毒性。我们的筛选表明，人类 CD2AP AD 易感基因的果蝇同源物 cindr 是 Tau 介导的疾病机制的调节剂。重要的是，我们还确定了 FERMT2 和 CELF1 的果蝇同源物作为 Tau 调节剂，并且这些基因座已在最新的 GWAS 荟萃分析中被独立验证为 AD 易感性基因座。CD2AP 和 FERMT2 先前都与细胞黏附作用有关，我们的筛选还确定了人类整合素黏附受体 ITGAM 和 ITGA9 的果蝇同源物作为 Tau 神经毒性的调节剂。我们的结果强调了细胞黏附途径在 Tau 毒性和 AD 易感性中的重要作用，并证明了模型生物遗传筛选在人类 GWAS 的功能后续研究中的强大功能。
