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

David O. Azorsa, Ri Lee H. Robeson, Danielle Frost, Bessie M. hoovet, Gillian R. Brautigam, Chad Dickey, Christian Beaudry, Gargi D. Basu, David R. Holz, Joseph A. Hernandez, Kristen M. Bisanz, Leslie Gwinn, Andrew Grover, Joseph Rogers, Eric M. Reiman, Michael Hutton, Dietrich A. Stephan, Spyro Mousses, Travis Dunckley

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Article number25
JournalBMC Genomics
Volume11
Issue number1
DOIs
StatePublished - Jan 12 2010

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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    Azorsa, D. O., Robeson, R. L. H., Frost, D., hoovet, B. M., Brautigam, G. R., Dickey, C., Beaudry, C., Basu, G. D., Holz, D. R., Hernandez, J. A., Bisanz, K. M., Gwinn, L., Grover, A., Rogers, J., Reiman, E. M., Hutton, M., Stephan, D. A., Mousses, S., & Dunckley, T. (2010). High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation. BMC Genomics, 11(1), [25]. https://doi.org/10.1186/1471-2164-11-25