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

Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of alpha-synuclein aggregates and-subsequent 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.

Automated summary

Parkinson's disease is caused by alpha-synuclein accumulation and death of dopamine neurons in the substantia nigra pars compacta, with NLRP3 inflammasome hyperactivation playing a role in the disease. Loss of parkin activity leads to spontaneous assembly of NLRP3 inflammasome in dopamine neurons, which is further exacerbated by mitochondrial-derived reactive oxygen species. Inhibition of neuronal NLRP3 inflammasome assembly can prevent degeneration of dopamine neurons in PD models.