Elevation of casein kinase 1 epsilon associated with TDP-43 and tau pathologies in Alzheimer's disease
Elevation of casein kinase 1 epsilon associated with TDP-43 and tau pathologies in Alzheimer's disease
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酪蛋白激酶 1 epsilon 升高与阿尔茨海默病中的 TDP-43 和 tau 病理学相关
DOI：
10.1111/bpa.12775
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发表时间：
2020
期刊：
影响因子：
6.4
通讯作者：
Liu Fei
中科院分区：
文献类型：
--
作者：
Gu Jianlan;Hu Wen;Tan Xuefeng;Qu Shuting;Chu D;an;Gong Cheng-Xin;Iqbal Khalid;Liu Fei
阿尔茨海默病 (AD) 的特征是大脑中存在细胞外 β 淀粉样蛋白斑块和神经元内过度磷酸化的微管相关蛋白 tau 的神经原纤维缠结。神经元细胞质中 43 kDa 的交互反应 DNA 结合蛋白 (TDP-43) 的聚集是 AD 的另一个特征。然而，TDP-43 如何与 AD 发病机制相关尚不清楚。在这里，我们发现酪蛋白激酶 1ε (CK1ε) 在 Ser403/404 和 Ser409/410 处磷酸化 TDP-43。在 AD 大脑中，CK1ε 水平显着升高，并与 TDP-43 Ser403/404 和 Ser409/410 磷酸化呈正相关。 CK1ε 的过度表达促进其细胞质聚集，并抑制 TDP-43 促进的 tau mRNA 不稳定和 tau 外显子 10 包含，导致 tau 和 3R-tau 表达增加。 CK1ε和TDP-43磷酸化水平与人脑中总tau和3R-tau水平呈正相关。此外，我们在初步免疫组织化学研究中观察到，严重的 tau 病理学伴随着强大的 TDP-43 病理学和高水平的 CK1ε。综上所述，我们的研究结果表明，AD 脑中 CK1ε 的升高可能会磷酸化 TDP-43，促进其细胞质聚集并抑制其在 tau mRNA 加工中的功能，从而导致 tau 病理学加速/恶化。因此，CK1ε 的升高可能将 TDP-43 与 AD 脑中的 tau 发病机制联系起来。
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.