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

BMC Genomics

Research Article

Joseph Rogers¹  Andrew Grover¹  Chad Dickey²  Michael Hutton³  Travis Dunckley⁴  Gillian R Brautigam⁴  Danielle Frost⁴  Bessie Meec hoovet⁴  RiLee H Robeson⁴  Dietrich A Stephan⁴  Eric M Reiman⁵  Gargi D Basu⁶  David R Holz⁶  Spyro Mousses⁶  David O Azorsa⁶  Leslie Gwinn⁶  Christian Beaudry⁶  Joseph A Hernandez⁶  Kristen M Bisanz⁶ 

[1] Center for Alzheimer's Research, Sun Health Research Institute, Sun City, Arizona, USA;Arizona Alzheimer's Consortium, Phoenix, AZ, USA;Department of Neurology, Mayo Clinic, Jacksonville, FL, USA;Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 8, 33612, Tampa, FL, USA;Department of Neurology, Mayo Clinic, Jacksonville, FL, USA;Senior Director, Neuroscience Drug Discovery, Merck and Co Ltd., BMB8-106, 33 Avenue Louis Pasteur, 02115, Boston, MA, USA;Neuorgenomics Division, Translational Genomics Research Institute, 85004, Phoenix, Arizona, USA;Arizona Alzheimer's Consortium, Phoenix, AZ, USA;Neuorgenomics Division, Translational Genomics Research Institute, 85004, Phoenix, Arizona, USA;Banner Alzheimer's Institute and Department of Psychiatry, University of Arizona, Phoenix, AZ, USA;Arizona Alzheimer's Consortium, Phoenix, AZ, USA;Pharmaceutical Genomics Division, Translational Genomics Research Institute, 85251, Scottsdale, Arizona, USA;

关键词: Eukaryotic Translation Initiation Factor;    12E8 Epitope;   

DOI  :  10.1186/1471-2164-11-25

 received in 2008-12-11, accepted in 2010-01-12,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundNeurofibrillary 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Azorsa et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.