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

• Published in: Acta neuropathologica Vol. 133; no. 6; pp. 955 - 966
• Main Authors: Chapuis, Julien, Flaig, Amandine, Grenier-Boley, Benjamin, Eysert, Fanny, Pottiez, Virginie, Deloison, Gaspard, Vandeputte, Alexandre, Ayral, Anne-Marie, Mendes, Tiago, Desai, Shruti, Goate, Alison M., Kauwe, John S. K., Leroux, Florence, Herledan, Adrien, Demiautte, Florie, Bauer, Charlotte, Checler, Fréderic, Petersen, Ronald C., Blennow, Kaj, Zetterberg, Henrik, Minthon, Lennart, Van Deerlin, Vivianna M., Lee, Virginia Man-Yee, Shaw, Leslie M., Trojanowski, John Q., Albert, Marilyn, Moghekar, Abhay, O’Brien, Richard, Peskind, Elaine R., Malmanche, Nicolas, Schellenberg, Gerard D., Dourlen, Pierre, Song, Ok-Ryul, Cruchaga, Carlos, Amouyel, Philippe, Deprez, Benoit, Brodin, Priscille, Lambert, Jean-Charles
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2017; Springer; Springer Nature B.V
• Subjects: Advertising executives; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Animals; Basic Medicine; Biomarkers - cerebrospinal fluid; Cell Membrane - metabolism; Cell surface; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebrospinal fluid; Disease susceptibility; Genetic aspects; Genetic Loci; Genetic Predisposition to Disease; Genetic screening; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; HEK293 Cells; Hippocampus - metabolism; Hippocampus - pathology; Humans; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Neurosciences; Neurovetenskaper; Original Paper; Pathology; Peptides; Protein turnover; Rats; RNA Interference; RNA, Small Interfering - genetics; siRNA; Aβ Peptide Levels; Under-expressed Genes; International Genomics Of Alzheimer’s Project (IGAP); Genome-wide Association Studies (GWAS); Late-onset AD (LOAD)
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-016-1652-z

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.