Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology.
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.
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
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P
Dourlen
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
F J
FJ
Fernandez-Gomez
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
C
C
Dupont
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
B
B
Grenier-Boley
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
C
C
Bellenguez
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
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H
Obriot
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
R
R
Caillierez
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
Y
Y
Sottejeau
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
J
J
Chapuis
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
A
A
Bretteville
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
F
F
Abdelfettah
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
C
C
Delay
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
N
N
Malmanche
Institute of Clinical Medicine-Neurology and Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
H
H
Soininen
Institute of Clinical Medicine-Neurology and Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.|Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
M
M
Hiltunen
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
M-C
MC
Galas
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.|Centre Hospitalier Régional Universitaire de Lille, Lille, France.
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0000-0001-9088-234X
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Amouyel
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
N
N
Sergeant
INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|Univ.Lille, JPArc, Lille, France.|CHRU, Memory Clinic, Lille, France.
L
L
Buée
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.
J-C
JC
Lambert
Institut Pasteur de Lille, Lille, France.|INSERM, UMR 1167, Lille, France.|Université de Lille, Lille, France.|Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
B
B
Dermaut
D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics; D051418:Focal Adhesion Kinase 2 / Q000235:genetics* / Q000378:metabolism; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D012307:Risk Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human