Key Laboratory of Neuroregeneration of Jiangsu Province and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, P. R. China.
Department of Genetics, School of Life Science, Nantong University, Nantong, Jiangsu, 226001, P. R. China.
Sci Rep. 2017 Oct 18;7(1):13478. doi: 10.1038/s41598-017-13791-5.
Hyperphosphorylation of tau and imbalanced expression of 3R-tau and 4R-tau as a result of dysregulation of tau exon 10 splicing are believed to be pivotal to the pathogenesis of tau pathology, but the molecular mechanism leading to the pathologic tau formation in Alzheimer's disease (AD) brain is not fully understood. In the present study, we found that casein kinase 1ε (CK1ε) was increased significantly in AD brains. Overexpression of CK1ε in cultured cells led to increased tau phosphorylation at many sites. Moreover, we found that CK1ε suppressed tau exon 10 inclusion. Levels of CK1ε were positively correlated to tau phosphorylation, 3R-tau expression and tau pathology, and negatively correlated to 4R-tau in AD brains. Overexpression of CK1ε in the mouse hippocampus increased tau phosphorylation and impaired spontaneous alternation behavior. These data suggest that CK1ε is involved in the regulation of tau phosphorylation, the alternative splicing of tau exon 10, and cognitive performance. Up-regulation of CK1ε might contribute to tau pathology by hyperphosphorylating tau and by dysregulating the alternative splicing of tau exon 10 in AD.
过度磷酸化的 tau 和 3R-tau 与 4R-tau 的表达失衡，是由于 tau 外显子 10 剪接的失调，被认为是 tau 病理学发病机制的关键，但阿尔茨海默病（AD）脑中导致病理性 tau 形成的分子机制尚未完全阐明。在本研究中，我们发现酪蛋白激酶 1ε（CK1ε）在 AD 脑中显著增加。在培养细胞中过表达 CK1ε 会导致 tau 在许多位点过度磷酸化。此外，我们发现 CK1ε 抑制 tau 外显子 10 的包含。AD 脑中 CK1ε 的水平与 tau 磷酸化、3R-tau 表达和 tau 病理学呈正相关，与 4R-tau 呈负相关。CK1ε 在小鼠海马中的过表达会增加 tau 磷酸化并损害自发交替行为。这些数据表明，CK1ε 参与 tau 磷酸化、tau 外显子 10 的选择性剪接以及认知表现的调节。CK1ε 的上调可能通过过度磷酸化 tau 和调节 AD 中 tau 外显子 10 的选择性剪接来促进 tau 病理学。
