Dataset Information

Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

ABSTRACT: 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.

SUBMITTER: Panicker N

PROVIDER: S-EPMC9357148 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

Panicker Nikhil N Kam Tae-In TI Wang Hu H Neifert Stewart S Chou Shih-Ching SC Kumar Manoj M Brahmachari Saurav S Jhaldiyal Aanishaa A Hinkle Jared T JT Akkentli Fatih F Mao Xiaobo X Xu Enquan E Karuppagounder Senthilkumar S SS Hsu Eric T ET Kang Sung-Ung SU Pletnikova Olga O Troncoso Juan J Dawson Valina L VL Dawson Ted M TM

Neuron 20220601 15

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 D ...[more]

PMID: 35654037

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Project description:Aberrant activation of the non-receptor kinase c-Abl is implicated in the development of pathogenic hallmarks of Parkinson's disease, such as α-synuclein aggregation and progressive neuronal loss. c-Abl-mediated phosphorylation and inhibition of parkin ligase function lead to accumulation of parkin interacting substrate (PARIS) that mediates α-synuclein pathology-initiated dopaminergic neurodegeneration. Here we show that, in addition to PARIS accumulation, c-Abl phosphorylation of PARIS is required for PARIS-induced cytotoxicity. c-Abl-mediated phosphorylation of PARIS at Y137 (within the Krüppel-associated box domain) drives its association with KAP1 and the repression of genes with diverse functions in pathways such as chromatin remodelling and p53-dependent cell death. One phosphorylation-dependent PARIS target, MDM4 (a p53 inhibitor that associates with MDM2; also known as MDMX), is transcriptionally repressed in a histone deacetylase-dependent manner via PARIS binding to insulin response sequence motifs within the MDM4 promoter. Virally induced PARIS transgenic mice develop c-Abl activity-dependent Parkinson's disease features such as motor deficits, dopaminergic neuron loss and neuroinflammation. PARIS expression in the midbrain resulted in c-Abl activation, PARIS phosphorylation, MDM4 repression and p53 activation, all of which are blocked by the c-Abl inhibitor nilotinib. Importantly, we also observed aberrant c-Abl activation and PARIS phosphorylation along with PARIS accumulation in the midbrain of adult parkin knockout mice, implicating c-Abl in recessive Parkinson's disease. Inhibition of c-Abl or PARIS phosphorylation by nilotinib or Y137F-PARIS expression in adult parkin knockout mice blocked MDM4 repression and p53 activation, preventing motor deficits and dopaminergic neurodegeneration. Finally, we found correlative increases in PARIS phosphorylation, MDM4 repression and p53 activation in post-mortem Parkinson's disease brains, pointing to clinical relevance of the c-Abl-PARIS-MDM4-p53 pathway. Taken together, our results describe a novel mechanism of epigenetic regulation of dopaminergic degeneration downstream of pathological c-Abl activation in Parkinson's disease. Since c-Abl activation has been shown in sporadic Parkinson's disease, PARIS phosphorylation might serve as both a useful biomarker and a potential therapeutic target to regulate neuronal loss in Parkinson's disease.

Dataset Information

Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

Publications

Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

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