Zou Wenkai, Kou Liang, Wang Yiming, Jin Zongjie, Xiong Nian, Wang Tao, Xia Yun
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
NPJ Parkinsons Dis. 2025 May 28;11(1):141. doi: 10.1038/s41531-025-01005-z.
Complement C4, implicated in neuroinflammation and synaptic dysfunction, plays a poorly defined role in Parkinson's disease (PD). Here, we demonstrate elevated C4 levels in PD patient plasma and the substantia nigra of α-synuclein preformed fibril (α-syn PFF)-injected mice, correlating with disease severity. α-syn PFF treatment induces complement C4 expression, particularly in neurons, with astrocytes further enhancing this response. Complement C4 was found to amplify astrocytic inflammatory responses, leading to increased neuronal apoptosis and synaptic damage. Additionally, conditioned media from astrocytes treated with α-syn PFF and complement C4 accelerated α-syn aggregation and synaptic loss in cultured neurons. In vivo, complement C4 exacerbated motor dysfunction, dopaminergic neuronal loss, and α-syn pathology in α-syn PFF-injected mice. These findings reveal that complement C4 significantly contributes to the neuroinflammatory environment and α-syn pathology in PD, highlighting its potential as a therapeutic target for mitigating neurodegeneration in this disorder.
补体C4与神经炎症和突触功能障碍有关，在帕金森病（PD）中作用尚不明确。在此，我们证明了PD患者血浆和注射了α-突触核蛋白预形成纤维（α-syn PFF）的小鼠黑质中C4水平升高，且与疾病严重程度相关。α-syn PFF处理可诱导补体C4表达，特别是在神经元中，星形胶质细胞可进一步增强这种反应。发现补体C4可放大星形胶质细胞的炎症反应，导致神经元凋亡增加和突触损伤。此外，用α-syn PFF和补体C4处理的星形胶质细胞的条件培养基加速了培养神经元中α-syn的聚集和突触丧失。在体内，补体C4加剧了注射α-syn PFF的小鼠的运动功能障碍、多巴胺能神经元丧失和α-syn病理改变。这些发现表明补体C4在PD的神经炎症环境和α-syn病理过程中起重要作用，突出了其作为减轻该疾病神经退行性变治疗靶点的潜力。
