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PD文献阅读第1期:Neuron—Parkin缺陷通过NLRP3炎症小体诱导DA神经元变性

2022-11-12 12:41

Neuron—Parkin缺陷通过NLRP3炎症小体诱导DA神经元变性


中文摘要

神经元内α-突触核蛋白聚集体的积累和随后黑质致密部(SNpc)多巴胺(DA)神经元的死亡参与了帕金森病(PD)的发生NOD样受体蛋白3NLRP3)炎性小体的小胶质细胞过度激活已在包括PD在内的各种神经退行性疾病中得到了充分的证明。研究人员发现,小鼠和人DA神经元中Parkin蛋白活性的丧失导致神经元NLRP3炎性小体的自发组装导致DA神经元死亡Parkin通常通过泛素化和利用蛋白酶体靶向降解NLRP3来抑制炎症小体启动Parkin活性的丧失会诱导另一种Parkin泛素化底物ZNF746/PARIS的积累,进而增加线粒体衍生的活性氧(mitoROS),从而导致活性NLRP3炎性小体复合物的组装。抑制神经元NLRP3炎性小体组装可防止家族性和散发性PD模型中DA神经元变性。旨在抑制神经元NLRP3炎症小体激活的策略有望成为PD的疾病治疗方法。

英文摘要

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.

参考文献:Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease. Neuron. 2022 Aug 3;110(15):2422-2437.e9. doi: 10.1016/j.neuron.2022.05.009. Epub 2022 Jun 1.

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