Azorsa et al. BMC Genomics 2010, 11:25 http://www.biomedcentral.com/1471-2164/11/25 R E S E A R C H A R T I C L E Open Access High-content siRNA screening of the kinome identifies kinases involved in Alzheimer’s disease-related tau hyperphosphorylation David O Azorsa2†, RiLee H Robeson1,6†, Danielle Frost1,6, Bessie Meec hoovet1,6, Gillian R Brautigam1,6, Chad Dickey3,8, Christian Beaudry2, Gargi D Basu2, David R Holz2, Joseph A Hernandez2, Kristen M Bisanz2, Leslie Gwinn2, Andrew Grover4,6, Joseph Rogers4,6, Eric M Reiman1,5,6, Michael Hutton3,7, Dietrich A Stephan1,6, Spyro Mousses2, Travis Dunckley1,6* 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 a 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. Background Alzheimer’s disease (AD) is a secondary tauopathy, gen- erally thought to result from the upstream effects of toxic amyloid aggregates. While there are a growing number of amyloid-modifying therapeutics in clinical trials, targeting amyloid alone may not be sufficient to mitigate the cognitive deficits that occur during the full course of AD[1]. Other targets, such as the tau and apo- lipoprotein E proteins, are thus being investigating for additional therapeutic development. However, the pro- teins through which amyloid signals to promote tau pathology in AD are a critical missing link that must be * Correspondence: tdunckley@tgen.org † Contributed equally 1Neuorgenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA connected to facilitate the development of tau-modifying AD treatments. In AD, tau protein becomes hyperphosphorylated and aggregates into paired helical filaments (PHF), the main component of NFTs [2-7]. Indeed, altered tau protein function has emerged as a key factor in many neurode- generative diseases, including AD[8,9]. Tau functions as a microtubule organizing protein that increases microtu- bule stability by suppressing dynamic instability[10]. Hyperphosphorylation of tau protein is thought to lead to microtubule instability, neurofibrillary tangle forma- tion, and loss of a functional microtubule cytoskeleton, contributing to neuronal cell dysfunction and cell death. In Alzheimer’s disease, sequential hyperphosphorylation of tau protein on multiple amino acids correlates with the severity of NFT pathology in affected brain regions © 2010 Azorsa et al; licensee 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.