C9ORF72-SMCR8复合物在小胶质细胞中的功能及其介导的炎症反应

C9ORF72基因中(GGGGCC)n异常扩增是导致家族性肌萎缩侧索硬化症（ALS）和额颞痴呆症（FTD）的最常见因素。C9ORF72缺失导致自噬溶酶体通路异常并参与疾病进程；C9ALS/FTD患者神经免疫细胞异常引起的神经炎症是致病因素之一。C9ORF72在神经免疫细胞中的功能及致病机理有待深入研究。我们前期结果显示C9ORF72-SMCR8复合物调控自噬-溶酶体通路；双基因突变体小鼠存在免疫缺陷及炎症反应，并且大脑中激活态神经免疫细胞（小胶质细胞）增加，表明复合物可能在神经炎症中发挥重要作用。因此，我们提出以下研究内容：1）小胶质细胞中C9ORF72-SMCR8复合物对自噬-溶酶体通路的调控；2）小胶质细胞中C9ORF72-SMCR8复合物参对炎症反应的调控；3）该复合物介导的小胶质细胞和神经元之间的互作。本研究将揭示C9ORF72复合物在小胶质细胞中的分子功能及其介导的神经炎症机制。

Hexanucleotide (GGGGCC)n repeat expansion in C9ORF72 is the main genetic cause of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS). The Loss-of-function of C9ORF72 results in immune dysregulation and impairs the autophagy-lysosome pathway, which is implicated in the C9ALS/FTD pathogenesis. The neuroinflammation in C9ALS/FTD patients caused by the abnormality of the neural-immune cells also leads to the disease. However, the molecular functions of C9ORF72 in the immune cells, especially microglial cells, are not well characterized. Our preliminary data show that: (i) C9ORF72-SMCR8 complex plays a role in the autophagy-lysosome pathway, (ii) Double KO mutant mice exhibit immune dysfunction and inflammation, and (iii) More activated microglial cells are detected in dKO mice brain. These data indicate that the C9ORF72-SMCR8 complex is required for the normal function of microglial cells. Therefore, the aims of this proposal are to: 1. determine the role of C9ORF72-SMCR8-containing complex in the autophagy-lysosome pathway of microglial cells; 2. explore the molecular functions of the complex in the neuro-inflammation of microglial cells; 3. dissect the interaction between C9ORF72-SMCR8 complex-mediated microglial cells and neurons. This study is expected to provide insights into fundamental mechanisms of neurodegeneration associated with autophagy-lysosome dysregulation in microglia that may ultimately lead to novel approaches for treating relevant neurodegenerative diseases.