Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Brain Pathol. 2020 Mar;30(2):283-297. doi: 10.1111/bpa.12775. Epub 2019 Aug 22.
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.
阿尔茨海默病（AD）的特征是大脑中存在细胞外淀粉样β斑块和神经元内过度磷酸化微管相关蛋白 tau 的神经原纤维缠结。转激活反应 DNA 结合蛋白 43 kDa（TDP-43）在神经元细胞质中的聚集是 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 位点磷酸化 TDP-43。在 AD 大脑中，CK1ε 的水平显著增加，并与 TDP-43 在 Ser403/404 和 Ser409/410 位点的磷酸化呈正相关。CK1ε 的过表达促进其细胞质聚集，并抑制 TDP-43 促进 tau mRNA 不稳定性和 tau 外显子 10 包含，导致 tau 和 3R-tau 表达增加。CK1ε 水平和 TDP-43 磷酸化水平与人类大脑中总 tau 和 3R-tau 的水平呈正相关。此外，我们在初步免疫组织化学研究中观察到，严重的 tau 病理学伴随着强烈的 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 大脑中 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，从而加速/加剧 tau 病理学。因此，CK1ε 的升高可能将 TDP-43 与 AD 大脑中的 tau 发病机制联系起来。
