Elevation of casein kinase 1ε associated with TDP-43 and tau pathologies in Alzheimer's disease.
Brain Pathol
; 30(2): 283-297, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31376192
Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid ß 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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
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Caseína Quinase 1 épsilon
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Proteínas de Ligação a DNA
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article