Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chapuis, J; Flaig, A; Grenier-Boley, B; Eysert, F; Pottiez, V; Deloison, G; Vandeputte, A; Ayral, A-M; 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-Y; Shaw, LM; Trojanowski, JQ; Albert, M; Moghekar, A; O'Brien, R; Peskind, ER; Malmanche, N; Schellenberg, GD; Dourlen, P; Song, O-R; Cruchaga, C; Amouyel, P; Deprez, B; Brodin, P; Lambert, J-C; ADGC, Alzheimer’s Disease Neuroimaging Initiative,

Published Date

  • June 2017

Published In

Volume / Issue

  • 133 / 6

Start / End Page

  • 955 - 966

PubMed ID

  • 27933404

Pubmed Central ID

  • 27933404

Electronic International Standard Serial Number (EISSN)

  • 1432-0533

International Standard Serial Number (ISSN)

  • 0001-6322

Digital Object Identifier (DOI)

  • 10.1007/s00401-016-1652-z

Language

  • eng