Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA.
Neuron. 2022 Aug 3;110(15):2422-2437.e9. doi: 10.1016/j.neuron.2022.05.009. Epub 2022 Jun 1.
Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.
帕金森病（PD）部分由α-突触核蛋白聚集体在神经元内的积累以及随后的黑质致密部多巴胺（DA）神经元死亡介导。NOD 样受体蛋白 3（NLRP3）炎症小体的小胶质细胞过度激活在各种神经退行性疾病中已有充分记录，包括 PD。我们在这里表明，在小鼠和人类 DA 神经元中 parkin 活性的丧失导致自发性神经元 NLRP3 炎症小体组装，导致 DA 神经元死亡。Parkin 通过泛素化和靶向 NLRP3 进行蛋白酶体降解来正常抑制炎症小体的引发。Parkin 活性的丧失还通过线粒体来源的活性氧（mitoROS）的产生，通过另一种 parkin 泛素化底物 ZNF746/PARIS 的积累，导致活性 NLRP3 炎症小体复合物的组装。抑制神经元 NLRP3 炎症小体组装可防止家族性和散发性 PD 模型中 DA 神经元的退化。旨在限制神经元 NLRP3 炎症小体激活的策略有望成为 PD 的一种疾病修饰治疗方法。
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