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Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology

(2017) MOLECULAR PSYCHIATRY. 22(6). p.874-883
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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.
Keywords
FOCAL ADHESION KINASE, TYROSINE PHOSPHORYLATION, SIGNALING PATHWAYS, CELL-DEATH, DISEASE, DROSOPHILA, MOUSE, NEURODEGENERATION, NEUROTOXICITY, ACTIVATION

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Chicago
Dourlen, P, FJ Fernandez-Gomez, C Dupont, B Grenier-Boley, C Bellenguez, H Obriot, R Caillierez, et al. 2017. “Functional Screening of Alzheimer Risk Loci Identifies PTK2B as an in Vivo Modulator and Early Marker of Tau Pathology.” Molecular Psychiatry 22 (6): 874–883.
APA
Dourlen, P., Fernandez-Gomez, F., Dupont, C., Grenier-Boley, B., Bellenguez, C., Obriot, H., Caillierez, R., et al. (2017). Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. MOLECULAR PSYCHIATRY, 22(6), 874–883.
Vancouver
1.
Dourlen P, Fernandez-Gomez F, Dupont C, Grenier-Boley B, Bellenguez C, Obriot H, et al. Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. MOLECULAR PSYCHIATRY. 2017;22(6):874–83.
MLA
Dourlen, P, FJ Fernandez-Gomez, C Dupont, et al. “Functional Screening of Alzheimer Risk Loci Identifies PTK2B as an in Vivo Modulator and Early Marker of Tau Pathology.” MOLECULAR PSYCHIATRY 22.6 (2017): 874–883. Print.
@article{8517770,
  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 {\textrangle}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.},
  author       = {Dourlen, P and Fernandez-Gomez, FJ and Dupont, C and Grenier-Boley, B and Bellenguez, C and Obriot, H and Caillierez, R and Sottejeau, Y and Chapuis, J and Bretteville, A and Abdelfettah, F and Delay, C and Malmanche, N and Soininen, H and Hiltunen, M and Galas, M-C and Amouyel, P and Sergeant, N and Bu{\'e}e, L and Lambert, J-C and Dermaut, Bart},
  issn         = {1359-4184},
  journal      = {MOLECULAR PSYCHIATRY},
  keyword      = {FOCAL ADHESION KINASE,TYROSINE PHOSPHORYLATION,SIGNALING PATHWAYS,CELL-DEATH,DISEASE,DROSOPHILA,MOUSE,NEURODEGENERATION,NEUROTOXICITY,ACTIVATION},
  language     = {eng},
  number       = {6},
  pages        = {874--883},
  title        = {Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology},
  url          = {http://dx.doi.org/10.1038/mp.2016.59},
  volume       = {22},
  year         = {2017},
}

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