School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, Queensland 4072, Australia.
UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Queensland 4092, Australia.
Sci Transl Med. 2018 Oct 31;10(465). doi: 10.1126/scitranslmed.aah4066.
Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.
帕金森病（PD）的特征是黑质中多巴胺能神经元的严重丧失，伴有慢性神经炎症、线粒体功能障碍以及广泛积累富含α-突触核蛋白的蛋白聚集体形成路易体。然而，将α-突触核蛋白病理学和多巴胺能神经元死亡与慢性小胶质细胞神经炎症联系起来的机制尚未完全阐明。我们表明，小胶质细胞 NOD 样受体家族含pyrin 结构域蛋白 3（NLRP3）炎性小体的激活是由纤维状α-突触核蛋白和多巴胺能变性触发的共同途径，而无α-突触核蛋白聚集体。在 PD 患者的大脑黑质中和多种临床前 PD 模型中，裂解的半胱天冬酶-1 和炎性小体衔接蛋白凋亡相关斑点样蛋白（ASC）都升高。纤维状α-突触核蛋白在小鼠小胶质细胞中激活 NLRP3，导致 NLRP3 炎性小体的延迟但强烈激活，从而导致细胞外白细胞介素-1β和 ASC 的释放，而无细胞焦亡。小分子 NLRP3 抑制剂 MCC950 的纳摩尔剂量可消除纤维状α-突触核蛋白介导的小鼠小胶质细胞中的炎性小体激活和细胞外 ASC 释放。此外，MCC950 在多种啮齿动物 PD 模型中的口服给药可抑制炎性小体激活，并有效减轻运动障碍、黑质纹状体多巴胺能变性和α-突触核蛋白聚集体的积累。这些发现表明，小胶质细胞 NLRP3 可能是持续的神经炎症来源，可驱动进行性多巴胺能神经病理学，并突出了 NLRP3 作为 PD 疾病修饰治疗的潜在靶标。
