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Open Access Highly Accessed Research article

High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation

David O Azorsa2, RiLee H Robeson16, Danielle Frost16, Bessie Meec hoovet16, Gillian R Brautigam16, Chad Dickey38, Christian Beaudry2, Gargi D Basu2, David R Holz2, Joseph A Hernandez2, Kristen M Bisanz2, Leslie Gwinn2, Andrew Grover46, Joseph Rogers46, Eric M Reiman156, Michael Hutton37, Dietrich A Stephan16, Spyro Mousses2 and Travis Dunckley16*

Author affiliations

1 Neuorgenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA

2 Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona, 85251, USA

3 Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

4 Center for Alzheimer's Research, Sun Health Research Institute, Sun City, Arizona, USA

5 Banner Alzheimer's Institute and Department of Psychiatry, University of Arizona, Phoenix, AZ, USA

6 Arizona Alzheimer's Consortium, Phoenix, AZ, USA

7 Senior Director, Neuroscience Drug Discovery, Merck and Co Ltd., BMB8-106, 33 Avenue Louis Pasteur, Boston MA 02115, USA

8 Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 8, Tampa, FL 33612, USA

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Citation and License

BMC Genomics 2010, 11:25  doi:10.1186/1471-2164-11-25

Published: 12 January 2010

Abstract

Background

Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments.

Results

We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.

Conclusions

These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.