title: High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation.
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 alpha 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.
authors.affiliation: Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona 85251, USA.
authors.forename: David O
authors.initials: DO
authors.lastname: Azorsa
authors.forename: RiLee H
authors.initials: RH
authors.lastname: Robeson
authors.forename: Danielle
authors.initials: D
authors.lastname: Frost
authors.forename: Bessie
authors.initials: B
authors.lastname: Meec hoovet
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Brautigam
authors.forename: Chad
authors.initials: C
authors.lastname: Dickey
authors.forename: Christian
authors.initials: C
authors.lastname: Beaudry
authors.forename: Gargi D
authors.initials: GD
authors.lastname: Basu
authors.forename: David R
authors.initials: DR
authors.lastname: Holz
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hernandez
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Bisanz
authors.forename: Leslie
authors.initials: L
authors.lastname: Gwinn
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Travis
authors.initials: T
authors.lastname: Dunckley
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000032:analysis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000032:analysis* / Q000235:genetics; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016875:tau Proteins; D011494:Protein Kinases