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

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

doi:10.1016/j.neuron.2022.05.009

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.

Authors

Nikhil Panicker¹, Tae-In Kam², Hu Wang³, Stewart Neifert⁴, Shih-Ching Chou⁵, Manoj Kumar¹, Saurav Brahmachari¹, Aanishaa Jhaldiyal⁶, Jared T Hinkle⁷, Fatih Akkentli⁴, Xiaobo Mao¹, Enquan Xu¹, Senthilkumar S Karuppagounder¹, Eric T Hsu⁸, Sung-Ung Kang¹, Olga Pletnikova⁹, Juan Troncoso¹⁰, Valina L Dawson¹¹, Ted M Dawson¹²

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁰ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: vdawson@jhmi.edu.
¹² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: tdawson@jhmi.edu.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding