小G蛋白RIT2对胞内α-突触核蛋白水平的调控作用及其对帕金森病发病的影响

Sporadic Parkinson's disease (PD) is a neurodegenerative disease caused by multiple factors. Previous and our studies have shown that RIT2 was decreased in the substantia nigra of PD patients, and its polymorphic loci rs12456492 (A/G; G as the risk allele) was associated with risk for PD. Our preliminary results showed that neuronal RIT2 expression was reduced when coupled with the G allele of rs12456492 and also in PD cellular and animal models. Meanwhile, we found that RIT2 negatively regulated intracellular levels of α-synuclein, which is the key PD-associated protein. However, it remains elusive how RIT2 regulates the intracellular levels of α-synuclein, and how this affects the pathogenesis of PD. Following analyses of our and reported data, in this study we aim to understand the above questions in the context of two potential pathways, CALM1 pathway and autophagy pathway, by applying multiple biochemical and molecular biology methods, and thereafter to explore related changes in peripheral blood samples of PD patients. Our findings will have new implications in understanding the mechanisms underlying sporadic PD pathogenesis, as well as the exploration of PD biomarkers.

散发性帕金森病（PD）是由多因素引起的神经退行性疾病。研究表明RIT2在PD患者的黑质区表达下降，且其遗传多态性与PD发病相关。课题组前期已发现rs12456492/G风险位点和PD造模均能引起神经细胞RIT2表达下降，且RIT2能负向调控胞内PD关键蛋白α-突触核蛋白的水平。然而，RIT2如何调控α-突触核蛋白的内在机制及其对PD发病的影响尚未清楚。本项目拟采用多种分子生物学方法，结合前期基础和国内外研究进展，针对CALM1介导途径和自噬-溶酶体通路就上述科学问题展开深入研究，并探索相关指标在PD外周血中的变化。研究成果对认识PD的发病机制和外周血指标带来新的启示。

帕金森病（PD）是多种因素引起的神经退行性疾病。多项研究表明小G蛋白RIT2与PD发病相关。本研究在前期研究基础上进行了探索。通过对C57BL/6小鼠不同组织的RIT2表达丰度检测发现，RIT2在黑质区含量高。接着在SH-SY5Y细胞系中，发现过表达或敲降RIT2能影响PD关键蛋白α-突触核蛋白水平，且是通过自噬途径调节的。进一步的研究发现RIT2主要是影响了自噬小体与溶酶体的融合而发挥作用。通过对RIT2的免疫共沉淀发现，RIT2与DDX5、BIP、PGAM5及HSC70存在相互作用。最后，通过敲除RIT2的小鼠行为研究发现，敲除RIT2小鼠有较好的运动能力。课题组将在此基础上进一步开展研究。