SNAREs复合体介导星形胶质细胞输出线粒体在帕金森病中的保护性作用及分子机制研究

帕金森病（PD）发病与线粒体功能障碍密切相关，目前尚无治愈手段。近年来发现的“线粒体转移”被认为是向疾病细胞补充线粒体的重要机制。我们报道了，人源诱导多能干细胞 （hiPSCs）分化的星形胶质细胞向PD模型中的多巴胺能（DA）神经元输送健康线粒体，并发挥神经保护作用。而星形胶质细胞作为线粒体供体，其输出线粒体的分子机制未明，亟待深入研究。我们进一步研究发现，星形胶质细胞向胞外释放线粒体，而SNAREs家族成员STX17、VAMP3和SNAP23分别敲减后，线粒体释放效率显著降低。由此提出假说：星形胶质细胞依赖SNAREs复合体的组装与解聚驱动线粒体释放，进而为PD模型中的DA神经元输送健康线粒体，修复受损的DA神经元。本项目将从动物、细胞、分子水平，系统阐明星形胶质细胞输出线粒体的分子机制及其神经保护作用，为PD治疗提供新靶点。

Parkinson's disease (PD) is closely related to mitochondrial dysfunction. However, there is no curative treatment. In recent years, the mitochondrial transfer is considered to be an important approach of supplement mitochondria to diseased cells. We have reported that human induced pluripotent stem cells (hiPSCs)-derived astrocytes protect dopaminergic (DA) neurons in the PD model by supplying healthy mitochondria. However, the mechanism of donating mitochondria is unclear. We further found functional mitochondria in astrocyte-derived conditioned medium, and the knockdown of SNAREs family members STX17, VAMP3, and SNAP23 significantly reduced the mitochondrial output. We next hypothesized that the assembly and depolymerization of the SNAREs complex drove the release of mitochondria, and then transferred healthy mitochondria to DA neurons in the PD model and played a protective role. This project will elucidate the molecular mechanism and neuroprotective effect of astrocytic mitochondria transfer in the animal, cellular, and molecular levels, which provides a new approach for PD.