Open AccessElevation of casein kinase 1ε associated with TDP‐43 and tau pathologies in Alzheimer's disease
Author(s) -
Gu Jianlan,
Hu Wen,
Tan Xuefeng,
Qu Shuting,
Chu Dandan,
Gong ChengXin,
Iqbal Khalid,
Liu Fei
Publication year - 2020
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12775
Subject(s) - casein kinase 1 , phosphorylation , pathogenesis , tau protein , kinase , alzheimer's disease , cytoplasm , chemistry , casein kinase 2 , biology , microbiology and biotechnology , neuroscience , pathology , medicine , protein kinase a , disease , cyclin dependent kinase 2
Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid β plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated microtubule‐associated protein tau in the brain. Aggregation of transactive response DNA‐binding protein of 43 kDa (TDP‐43) in the neuronal cytoplasm is another feature of AD. However, how TDP‐43 is associated with AD pathogenesis is unknown. Here, we found that casein kinase 1ε (CK1ε) phosphorylated TDP‐43 at Ser403/404 and Ser409/410. In AD brains, the level of CK1ε was dramatically increased and positively correlated with the phosphorylation of TDP‐43 at Ser403/404 and Ser409/410. Overexpression of CK1ε promoted its cytoplasmic aggregation and suppressed TDP‐43‐promoted tau mRNA instability and tau exon 10 inclusion, leading to an increase of tau and 3R‐tau expressions. Levels of CK1ε and TDP‐43 phosphorylation were positively correlated with the levels of total tau and 3R‐tau in human brains. Furthermore, we observed, in pilot immunohistochemical studies, that the severe tau pathology was accompanied by robust TDP‐43 pathology and a high level of CK1ε. Taken together, our findings suggest that the elevation of CK1ε in AD brain may phosphorylate TDP‐43, promote its cytoplasmic aggregation and suppress its function in tau mRNA processing, leading to acceleration/exacerbation of tau pathology. Thus, the elevation of CK1ε may link TDP‐43 to tau pathogenesis in AD brain.