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Mol Psychiatry. 2016 Apr 26. doi: 10.1038/mp.2016.59. [Epub ahead of print]

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

Author information

  • 1Institut Pasteur de Lille, Lille, France.
  • 2INSERM, UMR 1167, Lille, France.
  • 3Université de Lille, Lille, France.
  • 4INSERM, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
  • 5Univ.Lille, JPArc, Lille, France.
  • 6CHRU, Memory Clinic, Lille, France.
  • 7Institute of Clinical Medicine-Neurology and Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
  • 8Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  • 9Centre Hospitalier Régional Universitaire de Lille, Lille, France.
  • 10Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

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.Molecular Psychiatry advance online publication, 26 April 2016; doi:10.1038/mp.2016.59.

PMID:
27113998
DOI:
10.1038/mp.2016.59
[PubMed - as supplied by publisher]
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