TTBK1非激酶活性介导的自噬抑制在神经退行性疾病发生发展中的作用机制

TTBK1是一个在中枢神经系统中特异高表达的蛋白激酶。TTBK1可以磷酸化Tau和TDP-43，因此被报道与阿尔茨海默症、额颞叶变性和肌萎缩侧索硬化等神经退行性疾病密切相关。最近的研究发现TTBK1在小鼠大脑中过表达可引起显著的神经退行表型，但Tau/TDP-43的磷酸化未发生显著表达，提示有其他未知机制。申请人通过蛋白质亲和纯化质谱，鉴定到ATG8家族蛋白（GABARAP、GABARAPL1、GABARAPL2）是TTBK1的结合蛋白。功能实验证明TTBK1不能磷酸化GABARAPs，而是通过和GABARAPs蛋白的结合，抑制自噬体的形成，这一活性和激酶活性无关。鉴于自噬功能缺陷与神经退行性疾病的显著相关性，本研究提出TTBK1介导的自噬抑制是其促进神经退行性疾病分子机制之一的观点。

TTBK1 is a protein kinase that is a highly expressed in the central nervous system. TTBK1 can phosphorylate Tau and TDP-43 and has been reported to be closely associated with neurodegenerative diseases such as Alzheimer’s disease, frontotemporal degeneration and amyotrophic lateral sclerosis. Recent studies demonstrated that TTBK1 overexpression in the mouse brain can cause a significant neurodegenerative phenotype, but Tau/TDP-43 phosphorylation is not significantly altered, suggesting other mechanisms may involve in this process. AP-MS-based protein identification revealed that autophagy-related ATG8 proteins (GABARAP, GABARAPL1, GABARAPL2) as binding proteins of TTBK1. Functional experiments demonstrated that TTBK1 cannot phosphorylate GABARAPs, but inhibited the formation of autophagosomes by inhibited of GABARAPs-ULK1 interaction, which was independent of kinase activity. Given that significant correlations between autophagy dysfunction and neurodegenerative diseases, we proposed that TTBK1-mediated autophagy inhibition leads to neurodegenerative diseases.