Elevation of casein kinase 1ε associated with TDP-43 and tau pathologies in Alzheimer's disease.

Abstract

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.

• Authors: Jianlan Gu, Wen Hu, Xuefeng Tan, Shuting Qu, Dandan Chu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 30 Issue 2 Pg. 283-297 (03 2020) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 31376192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 International Society of Neuropathology.

Chemical References

• DNA-Binding Proteins
• MAPT protein, human
• TARDBP protein, human
• tau Proteins
• Casein Kinase 1 epsilon

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism, pathology)
• Brain (metabolism, pathology)
• Casein Kinase 1 epsilon (metabolism)
• DNA-Binding Proteins (metabolism)
• Female
• Humans
• Inclusion Bodies (metabolism, pathology)
• Male
• Phosphorylation
• Protein Aggregation, Pathological (metabolism, pathology)
• tau Proteins (metabolism)