High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation.
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.
Azorsa
David O
DO
Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona 85251, USA.
Robeson
RiLee H
RH
Frost
Danielle
D
Meec hoovet
Bessie
B
Brautigam
Gillian R
GR
Dickey
Chad
C
Beaudry
Christian
C
Basu
Gargi D
GD
Holz
David R
DR
Hernandez
Joseph A
JA
Bisanz
Kristen M
KM
Gwinn
Leslie
L
Grover
Andrew
A
Rogers
Joseph
J
Reiman
Eric M
EM
Hutton
Michael
M
Stephan
Dietrich A
DA
Mousses
Spyro
S
Dunckley
Travis
T
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*
D034741:RNA, Small Interfering; D016875:tau Proteins; D011494:Protein Kinases