酪蛋白激酶1ε在阿尔茨海默病TDP-43病理与tau病理关联中的作用及机制

In addition to neurofibrillary tangles of abnormally hyperphosphorylated tau and amyloid plaques of β-amyloid peptides, aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in the neuronal cytoplasm is another feature of Alzheimer’s disease (AD). However, whether and how TDP-43 and tau pathologies are linked in AD is unknown. We recently found that TDP-43 promotes the alternative splicing of tau exon 10 via binding with intron 9 of tau pre-mRNA, and increases 4R-tau expression. TDP-43 also binds with (UG)n elements of the 3’-untranslated region of tau mRNA and promotes tau mRNA degradation and decreases tau expression. We also found that casein kinase 1ε (CK1ε) phosphorylates and regulates TDP-43 function, suggesting that it may link TDP-43 pathology to tau pathology. In this project, we propose to investigate 1) the phosphorylation sites of TDP-43 by CK1ε and the subsequent effect on its subcellular localization and intracellular aggregation, 2) the effect of CK1ε on TDP-43-mediated tau mRNA stability, 3) the effect of CK1ε on TDP-43-promoted tau exon 10 alternative splicing, and 4) the effect of CK1ε on tau expression, alternative splicing of tau and tau pathology in vivo. These studies will include comprehensive investigations at molecular, cellular, and in vivo levels. The completion of the proposed project will unravel the molecular mechanism underlying the link between TDP-43 pathology and tau pathology in AD, and thus may provide new target for the prevention and treatment of tau-related neurodegenerative diseases like AD.

神经元胞质中TDP-43聚集是阿尔茨海默病(AD)脑内除异常过度磷酸化tau形成的神经原纤维缠结和β淀粉样蛋白聚集的老年斑外又一病理特征。约2/3的AD脑内TDP-43病理与tau病理共存，但机制不明。我们前期工作显示TDP-43促进tau mRNA的不稳定和tau外显子10编码、酪蛋白激酶1ε(CK1ε)磷酸化TDP-43、AD患者脑内tau病理与TDP-43病理的程度呈正相关，因此CK1ε很可能是二者关联的纽带。本项目将在分子、细胞和体内水平，从TDP-43磷酸化和亚细胞定位与胞质聚集、TDP-43介导的tau mRNA稳定性和tau外显子10可变剪接等角度，探讨CK1ε磷酸化TDP-43对tau表达、tau变异体表达和tau病理发生发展的影响。本项目的完成将可能揭示TDP-43在AD患者脑内tau病理发生发展中作用的新机制，为探寻AD及相关神经退行性病变防治新分子靶点提供重要科学依据

神经元胞质中交互反应DNA结合蛋白（TDP-43）的聚集是阿尔茨海默病（AD）脑内除异常过度磷酸化的tau蛋白聚集形成的神经原纤维缠结和β淀粉样蛋白聚集形成的老年斑之外的又一病理特征。约2/3的AD患者脑内TDP-43病理与tau病理共存，但具体机制尚不清楚。本项目在分子、细胞和体内水平，研究了CK1ε对TDP-43的磷酸化及对其亚细胞定位和细胞内聚集和tau mRNA加工的影响，及AD脑中上调的CK1ε在TDP-43病理和tau病理改变中的作用，探讨CK1ε在AD患者TDP-43病理与tau病理关联中的作用及机制。我们发现：1）CK1ε磷酸化TDP-43的Ser379、Ser403/404、Ser409/410位点，磷酸化作用呈位点特异性相互促进；2）CK1ε磷酸化TDP-43促进其细胞质转位并聚集；3）CK1ε抑制TDP-43对tau mRNA加工的调节；4）AD患者脑中CK1ε、磷酸化的TDP-43和total tau、3R-tau水平呈正相关。在AD患者脑中，CK1ε表达水平增加，TDP-43磷酸化水平增加，并与总tau和3R-tau的表达增加相关，CK1ε的表达增加与TDP-43病理和tau病理相关。本研究揭示CK1ε在AD患者脑内TDP-43 和tau病理发生发展中作用的新机制，为探寻AD及tau相关神经退行性病变防治新分子靶点提供重要科学依据。