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Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease
Neuron ( IF 14.7 ) Pub Date : 2022-06-01 , DOI: 10.1016/j.neuron.2022.05.009
Nikhil Panicker 1 , Tae-In Kam 2 , Hu Wang 3 , Stewart Neifert 4 , Shih-Ching Chou 5 , Manoj Kumar 1 , Saurav Brahmachari 1 , Aanishaa Jhaldiyal 6 , Jared T Hinkle 7 , Fatih Akkentli 4 , Xiaobo Mao 1 , Enquan Xu 1 , Senthilkumar S Karuppagounder 1 , Eric T Hsu 8 , Sung-Ung Kang 1 , Olga Pletnikova 9 , Juan Troncoso 10 , Valina L Dawson 11 , Ted M Dawson 12
Affiliation  

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.



中文翻译:


神经元 NLRP3 是一种帕金底物,可驱动帕金森病的神经退行性变



帕金森病 (PD) 部分是由 α-突触核蛋白聚集体在神经元内积累以及随后黑质致密部 (SNpc) 中的多巴胺 (DA) 神经元死亡介导的。 NOD 样受体蛋白 3 (NLRP3) 炎症小体的小胶质细胞过度激活已在多种神经退行性疾病(包括 PD)中得到充分证实。我们在此表明​​,小鼠和人类 DA 神经元中 Parkin 活性的丧失会导致自发的神经元 NLRP3 炎性体组装,从而导致 DA 神经元死亡。 Parkin 通常通过泛素化和靶向 NLRP3 进行蛋白酶体降解来抑制炎症小体引发。 Parkin 活性的丧失还会通过另一种 Parkin 泛素化底物 ZNF746/PARIS 的积累,通过线粒体衍生的活性氧 (mitoROS) 的产生,促进活性 NLRP3 炎性体复合物的组装。抑制神经元 NLRP3 炎性体组装可防止家族性和散发性 PD 模型中 DA 神经元的变性。旨在限制神经元 NLRP3 炎性体激活的策略有望成为帕金森病的疾病缓解疗法。

更新日期:2022-06-01
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