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Elevation of casein kinase 1ε associated with TDP-43 and tau pathologies in Alzheimer's disease.
Gu, Jianlan; Hu, Wen; Tan, Xuefeng; Qu, Shuting; Chu, Dandan; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei.
Afiliação
  • Gu J; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY.
  • Hu W; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
  • Tan X; Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China.
  • Qu S; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY.
  • Chu D; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY.
  • Gong CX; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
  • Iqbal K; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
  • Liu F; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas tau / Caseína Quinase 1 épsilon / Proteínas de Ligação a DNA / Doença de Alzheimer Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas tau / Caseína Quinase 1 épsilon / Proteínas de Ligação a DNA / Doença de Alzheimer Idioma: En Ano de publicação: 2020 Tipo de documento: Article