Abstract:
Parkinson\'s disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin+/- mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin+/- mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson\'s disease.
摘要:
帕金森病(PD)的特征是黑质致密部多巴胺能神经元的严重丧失,导致运动障碍。PD的发作通常伴有神经炎症和α-突触核蛋白聚集,广泛的研究集中在PD中的小胶质细胞NLRP3炎性体的激活,促进多巴胺能神经元的死亡.在这项研究中,通过双侧脑室注射LPS,在野生型和Parkin+/-小鼠中建立了脑炎症反应模型。在野生型小鼠中LPS诱导的NLRP3炎性体的激活促进PD的进展。在注射LPS的野生小鼠中使用MCC950诱导Parkin/PINK的激活并改善自噬,这反过来又提高了线粒体的周转。它还能抑制LPS诱导的炎症反应,改善电机功能,保护多巴胺能神经元,并抑制小胶质细胞的激活.此外,Parkin+/-小鼠表现出运动功能障碍,多巴胺能神经元的丢失,激活NLRP3炎性体,和α-突触核蛋白在早期开始聚集。Parkin+/-小鼠表现出更明显的小胶质细胞激活,更大的NLRP3炎性体激活,更严重的自噬功能障碍,与野生型小鼠相比,注射LPS后运动功能障碍更为明显。值得注意的是,在Parkin+/-小鼠中使用MCC950不能改善NLRP3炎性体激活,自噬功能障碍,或α-突触核蛋白聚集。因此,MCC950只能在Parkin/PINK1存在下发挥其作用,靶向Parkin介导的NLRP3炎性体激活有望成为帕金森病的潜在治疗策略。