RRC ID 40031
Author Dourlen P, Fernandez-Gomez FJ, Dupont C, Grenier-Boley B, Bellenguez C, Obriot H, Caillierez R, Sottejeau Y, Chapuis J, Bretteville A, Abdelfettah F, Delay C, Malmanche N, Soininen H, Hiltunen M, Galas MC, Amouyel P, Sergeant N, Buée L, Lambert JC, Dermaut B.
Title Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology.
Journal Mol. Psychiatry
Abstract A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS (CASS4), Eph (EPHA1), Fak (PTK2B) and Rab3-GEF (MADD) as Tau toxicity modulators. Of these, the focal adhesion kinase Fak behaved as a strong Tau toxicity suppressor in both the eye and an independent focal adhesion-related wing blister assay. Accordingly, the human Tau and PTK2B proteins biochemically interacted in vitro and PTK2B co-localized with hyperphosphorylated and oligomeric Tau in progressive pathological stages in the brains of AD patients and transgenic Tau mice. These data indicate that PTK2B acts as an early marker and in vivo modulator of Tau toxicity.
Volume 22(6)
Pages 874-883
Published 2017-6
DOI 10.1038/mp.2016.59
PII mp201659
PMID 27113998
PMC PMC5444024
MeSH Alzheimer Disease / genetics Animals Biomarkers Disease Models, Animal Drosophila / genetics Focal Adhesion Kinase 2 / genetics* Focal Adhesion Kinase 2 / metabolism Genetic Loci / genetics Genetic Predisposition to Disease / genetics Genome-Wide Association Study Humans Risk Factors tau Proteins / genetics tau Proteins / metabolism*
IF 11.64
Times Cited 3
Drosophila 7899R-2 8604R-1 8604R-2 3546R-1 8276R-2 8276R-3 1090R-1 1090R-2 10920R-2 10920R-3 12079R-1 12079R-4 1239R-4 14805R-1 3491R-2 3491R-3 9117R-1 9117R-7 10241R-1 10241R-3 10248R-1 10248R-2 3050R-2 4486R-1 4486R-4 11466R-3 3365R-2 1765R-2 1765R-4 1511R-1 1511R-3 3799R-2 3799R-3 7729R-2 7729R-3 10545R-3 2520R-1 2520R-2 1429R-1 1429R-3 6851R-3 12414R-1 12414R-3 5610R-1 5610R-2 4738R-2 4738R-3 1212R-2 1212R-3 12013R-2 12013R-3 10371R-1 3373R-2 3373R-4 3423R-3 13916R-3 1903R-3 15694R-1 15694R-2 32211R-7 9348R-2 32018R-1 32018R-3