- Home
- About
- Collaborative Data Access (SAGs)
- Publications
- For Members
Title | Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism. |
Publication Type | Journal Article |
Year of Publication | 2017 |
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 VMan-Yee, 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 |
Corporate Authors | ADGC, Alzheimer’s Disease Neuroimaging Initiative |
Journal | Acta Neuropathol |
Volume | 133 |
Issue | 6 |
Pagination | 955-966 |
Date Published | 2017 06 |
ISSN | 1432-0533 |
Keywords | Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Biomarkers, Cell Membrane, Cerebral Cortex, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, HEK293 Cells, Hippocampus, Humans, Membrane Proteins, Neoplasm Proteins, Neurons, Rats, RNA Interference, RNA, Small Interfering |
Abstract | 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. |
DOI | 10.1007/s00401-016-1652-z |
Alternate Journal | Acta Neuropathol. |
PubMed ID | 27933404 |
PubMed Central ID | PMC5427165 |
Grant List | K01 AG030514 / AG / NIA NIH HHS / United States R01 AG054060 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States R01 AG044546 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG042611 / AG / NIA NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States |