TY - JOUR
T1 - Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
AU - ADGC, Alzheimer’s Disease Neuroimaging Initiative
AU - Chapuis, Julien
AU - Flaig, Amandine
AU - Grenier-Boley, Benjamin
AU - Eysert, Fanny
AU - Pottiez, Virginie
AU - Deloison, Gaspard
AU - Vandeputte, Alexandre
AU - Ayral, Anne Marie
AU - Mendes, Tiago
AU - Desai, Shruti
AU - Goate, Alison M.
AU - Kauwe, John S.K.
AU - Leroux, Florence
AU - Herledan, Adrien
AU - Demiautte, Florie
AU - Bauer, Charlotte
AU - Checler, Fréderic
AU - Petersen, Ronald C.
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Minthon, Lennart
AU - Van Deerlin, Vivianna M.
AU - Lee, Virginia Man Yee
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Albert, Marilyn
AU - Moghekar, Abhay
AU - O’Brien, Richard
AU - Peskind, Elaine R.
AU - Malmanche, Nicolas
AU - Schellenberg, Gerard D.
AU - Dourlen, Pierre
AU - Song, Ok Ryul
AU - Cruchaga, Carlos
AU - Amouyel, Philippe
AU - Deprez, Benoit
AU - Brodin, Priscille
AU - Lambert, Jean Charles
N1 - Publisher Copyright:
© 2016, The Author(s).
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028025956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028025956&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1652-z
DO - 10.1007/s00401-016-1652-z
M3 - Article
C2 - 27933404
AN - SCOPUS:85028025956
SN - 0001-6322
VL - 133
SP - 955
EP - 966
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 6
ER -