NLRP3 Inflammasome Inhibition Prevents α-Synuclein Pathology by Relieving Autophagy Dysfunction in Chronic MPTP–Treated NLRP3 Knockout Mice

Zhou Ou, Yuanzhang Zhou, Lijun Wang, Liujun Xue, Jinlong Zheng, Liam Chen, Qiang Tong

Research output: Contribution to journalArticlepeer-review

Abstract

Recent researches showed that nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome inhibition exerted dopaminergic neuroprotection in cellular or animal models of Parkinson’s disease (PD). NLRP3 inflammasome has been proposed as a drug target for treatment of PD. However, the interplay between chronic NLRP3 inflammasome and progressive α-synuclein pathology keeps poorly understood. Moreover, the potential mechanism keeps unknown. In the present study, we investigate whether NLRP3 inflammasome inhibition prevents α-synuclein pathology by relieving autophagy dysfunction in the chronic 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD. NLRP3 knockout mice and their wild-type counterparts were treated with continuous MPTP administration via osmotic mini-pumps. Dopaminergic neuronal degeneration was assessed by western blotting and immunohistochemistry (IHC). The levels of dopamine and its metabolites were determined using high-performance liquid chromatography. NLRP3 inflammasome activation and autophagy biomarkers were assessed by western blot. The expressions of pro-inflammatory cytokines were measured by ELISA. The glial reaction and α-synuclein pathology were assessed by IHC and immunofluorescence. Our results show that NLRP3 inflammasome inhibition via NLRP3 knockout not only protects against nigral dopaminergic degeneration and striatal dopamine deletion but also prevents nigral pathological α-synuclein formation in PD mice. Furthermore, it significantly suppresses MPTP-induced glial reaction accompanied by the secretion of pro-inflammatory cytokines in the midbrain of mice. Most importantly, it relieves autophagy dysfunction in the midbrain of PD mice. Collectively, we demonstrate for the first time that improving autophagy function is involved in the preventive effect of NLRP3 inflammasome inhibition on α-synuclein pathology in PD.

Original languageEnglish (US)
Pages (from-to)1303-1311
Number of pages9
JournalMolecular neurobiology
Volume58
Issue number4
DOIs
StatePublished - Apr 2021
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by grants from the National Natural Science Foundation of China (No. 81600981), the Natural Science Foundation of Jiangsu Province (BK20191212), the Six Talent Peaks Project in Jiangsu Province (WSN-282), and the 533 Talent Project of Huai’an City (HAA201749).

Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • Autophagy
  • NLRP3
  • Neuroinflammation
  • Parkinson's disease
  • α-Synuclein pathology

PubMed: MeSH publication types

  • Journal Article

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