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.


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.

Keywords: Caspase-1; NLRP3; PARIS; Parkinson’s disease; ZNF746; inflammasome; neurodegeneration; parkin; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • NLR Proteins / metabolism
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Repressor Proteins / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Repressor Proteins
  • ZNF746 protein, human
  • Ubiquitin-Protein Ligases
  • parkin protein