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Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease

Microglial hyperactivation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD...

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Autores principales: Yan, Yi‐Qun, Zheng, Ran, Liu, Yi, Ruan, Yang, Lin, Zhi‐Hao, Xue, Nai‐Jia, Chen, Ying, Zhang, Bao‐Rong, Pu, Jia‐Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265164/
https://www.ncbi.nlm.nih.gov/pubmed/37029500
http://dx.doi.org/10.1111/acel.13834
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author Yan, Yi‐Qun
Zheng, Ran
Liu, Yi
Ruan, Yang
Lin, Zhi‐Hao
Xue, Nai‐Jia
Chen, Ying
Zhang, Bao‐Rong
Pu, Jia‐Li
author_facet Yan, Yi‐Qun
Zheng, Ran
Liu, Yi
Ruan, Yang
Lin, Zhi‐Hao
Xue, Nai‐Jia
Chen, Ying
Zhang, Bao‐Rong
Pu, Jia‐Li
author_sort Yan, Yi‐Qun
collection PubMed
description Microglial hyperactivation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild‐type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48‐linked polyubiquitination in microglia. The loss of Parkin activity in LPS‐induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin‐induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin‐mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD.
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spelling pubmed-102651642023-06-15 Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease Yan, Yi‐Qun Zheng, Ran Liu, Yi Ruan, Yang Lin, Zhi‐Hao Xue, Nai‐Jia Chen, Ying Zhang, Bao‐Rong Pu, Jia‐Li Aging Cell Research Articles Microglial hyperactivation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild‐type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48‐linked polyubiquitination in microglia. The loss of Parkin activity in LPS‐induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin‐induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin‐mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD. John Wiley and Sons Inc. 2023-04-07 /pmc/articles/PMC10265164/ /pubmed/37029500 http://dx.doi.org/10.1111/acel.13834 Text en © 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Yan, Yi‐Qun
Zheng, Ran
Liu, Yi
Ruan, Yang
Lin, Zhi‐Hao
Xue, Nai‐Jia
Chen, Ying
Zhang, Bao‐Rong
Pu, Jia‐Li
Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title_full Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title_fullStr Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title_full_unstemmed Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title_short Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
title_sort parkin regulates microglial nlrp3 and represses neurodegeneration in parkinson's disease
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265164/
https://www.ncbi.nlm.nih.gov/pubmed/37029500
http://dx.doi.org/10.1111/acel.13834
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