氨基酸诱导的mTORC1信号通路参与SCA3/MJD发病的作用机制

细胞自噬的功能障碍在神经退行性疾病中扮演重要作用，近年的研究表明受氨基酸诱导的mTORC1信号通路是调节自噬和溶酶体生成的主要途径之一，但是其是否参与SCA3/MJD发病依然尚未完全阐明。在本项目中我们将分析ataxin-3这一SCA3/MJD的致病蛋白在mTORC1-TFEB信号轴调节的自噬-溶酶体系统中的作用。我们的前期结果发现ataxin-3可以调节mTORC1上游的亮氨酸感受器Sestrin2的蛋白含量，并且以依赖于Sestrin2的方式调控亮氨酸诱导的mTORC1信号以及TFEB介导的细胞自噬。我们拟运用分子遗传学结合细胞生物学和生物化学技术，在细胞和在体水平深入研究ataxin-3调控mTORC1-TFEB信号轴介导的自噬的相应分子机制，分析ataxin-3的病理突变是否会影响这种调控，并探索此调控在SCA3/MJD这种常染色体显性遗传病发生发展中的意义。

Autophagic dysfunction plays an important role in neurodegenerative diseases, and recent studies have shown that amino acid-induced mTORC1 signaling is the main pathway for regulating autophagy and lysosomal biogenesis. However, whether this pathway plays a role in the pathogenesis of SCA3/MJD remains not fully understood. In this study we will explore the role of ataxin-3, the disease-causing protein of SCA3/MJD, in mTORC1-TFEB-regulated autophagy-lysosome system. Our preliminary data show that ataxin-3 can regulate the protein level of Leucine sensor Sestrin2, which is an upstream regulator of mTORC1. We also find that ataxin-3 can regulate Leucine-induced mTORC1 signaling and TFEB-mediated autophagy through Sestrin2. We will use molecular genetic approaches, cell biology and biochemistry to further investigate the molecular mechanism underlying mTORC1-TFEB-mediated autophagy driven by ataxin-3, analyze the effect of ataxin-3 pathogenic mutation on this regulation, and explore the role of this regulation in disease pathogenesis of autosomal dominant inherited SCA3/MJD.