Department of Neurology and Neurological Rehabilitation, Shanghai Disabled Persons' Federation Key Laboratory of Intelligent Rehabilitation Assistive Devices and Technologies, Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China.
Neurotoxin Research Center, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
J Neuroinflammation. 2024 Sep 28;21(1):246. doi: 10.1186/s12974-024-03234-0.
The primary pathological change in Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra. Additionally, excessive microglial activation and synaptic loss are also typical features observed in PD samples. Exercise trainings have been proven to improve PD symptoms, delay the disease progression as well as affect excessive microglial synaptic phagocytosis. In this study, we established a mouse model of PD by injecting mouse-derived α-synuclein preformed fibrils (M-α-syn PFFs) into the substantia nigra, and demonstrated that treadmill exercise inhibits microglial activation and synaptic phagocytosis in striatum. Using RNA-Seq and proteomics, we also found that PD involves excessive activation of the complement pathway which is closely related to over-activation of microglia and abnormal synaptic function. More importantly, exercise training can inhibit complement levels and complement-mediated microglial phagocytosis of synapses. It is probably triggered by CD55, as we observed that CD55 in the striatum significantly increased after exercise training and up-regulation of that molecule rescued motor deficits of PD mice, accompanied with reduced microglial synaptic phagocytosis in the striatum. This research elucidated the interplay among microglia, complement, and synapses, and analyzed the effects of exercise training on these factors. Our work also suggested CD55 as a complement-relevant candidate molecule for developing therapeutic strategies of PD.
帕金森病（PD）的主要病理学变化是黑质中多巴胺能神经元的进行性退化。此外，过度的小胶质细胞激活和突触丢失也是 PD 样本中的典型特征。运动训练已被证明可以改善 PD 症状，延缓疾病进展，并影响过度的小胶质细胞突触吞噬作用。在这项研究中，我们通过将源自小鼠的α-突触核蛋白原纤维（M-α-syn PFFs）注射到黑质中来建立 PD 小鼠模型，并证明跑步机运动抑制纹状体中小胶质细胞的激活和突触吞噬作用。通过 RNA-Seq 和蛋白质组学，我们还发现 PD 涉及补体途径的过度激活，这与小胶质细胞的过度激活和异常突触功能密切相关。更重要的是，运动训练可以抑制补体水平和补体介导的突触小胶质细胞吞噬作用。这可能是由 CD55 触发的，因为我们观察到运动训练后纹状体中的 CD55 明显增加，并且该分子的上调挽救了 PD 小鼠的运动缺陷，伴随着纹状体中小胶质细胞突触吞噬作用的减少。这项研究阐明了小胶质细胞、补体和突触之间的相互作用，并分析了运动训练对这些因素的影响。我们的工作还表明 CD55 作为一种与补体相关的候选分子，可用于开发 PD 的治疗策略。
