Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.
Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.
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DOI：
10.1007/s00401-016-1652-z
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发表时间：
2017-06
影响因子：
12.7
通讯作者：
ADGC, Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Chapuis J;Flaig A;Grenier-Boley B;Eysert F;Pottiez V;Deloison G;Vandeputte A;Ayral AM;Mendes T;Desai S;Goate AM;Kauwe JSK;Leroux F;Herledan A;Demiautte F;Bauer C;Checler F;Petersen RC;Blennow K;Zetterberg H;Minthon L;Van Deerlin VM;Lee VM;Shaw LM;Trojanowski JQ;Albert M;Moghekar A;O'Brien R;Peskind ER;Malmanche N;Schellenberg GD;Dourlen P;Song OR;Cruchaga C;Amouyel P;Deprez B;Brodin P;Lambert JC;ADGC, Alzheimer’s Disease Neuroimaging Initiative
全基因组关联研究（GWASs）已经确定了19个阿尔茨海默病（AD）的易感基因座。然而，了解这些基因如何参与AD的病理生理学是“后GWAS”时代的主要挑战之一。至少有123个基因位于19个易感基因座内;因此，传统的方法（逐个研究基因）将不具有时间和成本效益。因此，我们开发了一种全基因组，高含量的siRNA筛选方法，并使用它来评估基因表达不足对APP代谢的功能影响。我们发现有832个基因调节APP代谢。其中8个基因位于AD易感基因座内。在2886例AD患者中，只有FERMT 2（β3-整合素共激活剂）与脑脊液Aβ肽水平的变化显著相关。最后，我们发现FERMT 2的低表达通过提高细胞表面成熟APP的水平并促进其再循环来增加Aβ肽的产生。总的来说，我们的数据表明，FERMT 2通过调节APP代谢和Aβ肽的产生来调节AD风险。本文的在线版本（doi：10.1007/s 00401 -016-1652-z）包含补充材料，可供授权用户使用。
Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production. The online version of this article (doi:10.1007/s00401-016-1652-z) contains supplementary material, which is available to authorized users.