Neuronal NLRP3 is a Parkin Substrate That Drives Neurodegeneration in Parkinson's Disease

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2022 Jun 2

PMID 35654037

Authors

Nikhil Panicker

Tae-In Kam

Hu Wang

Stewart Neifert

Shih-Ching Chou

Manoj Kumar

Saurav Brahmachari

Aanishaa Jhaldiyal

Jared T Hinkle

Fatih Akkentli

Xiaobo Mao

Enquan Xu

Senthilkumar S Karuppagounder

Eric T Hsu

Sung-Ung Kang

Olga Pletnikova

Juan Troncoso

Valina L Dawson

Ted M Dawson

Affiliations

Soon will be listed here.

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.

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