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ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities

BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson’s disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD...

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Autores principales: Zheng, Ran, Yan, Yiqun, Dai, Shaobing, Ruan, Yang, Chen, Ying, Hu, Chenjun, Lin, Zhihao, Xue, Naijia, Song, Zhe, Liu, Yi, Zhang, Baorong, Pu, Jiali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899382/
https://www.ncbi.nlm.nih.gov/pubmed/36740674
http://dx.doi.org/10.1186/s12974-023-02709-w
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author Zheng, Ran
Yan, Yiqun
Dai, Shaobing
Ruan, Yang
Chen, Ying
Hu, Chenjun
Lin, Zhihao
Xue, Naijia
Song, Zhe
Liu, Yi
Zhang, Baorong
Pu, Jiali
author_facet Zheng, Ran
Yan, Yiqun
Dai, Shaobing
Ruan, Yang
Chen, Ying
Hu, Chenjun
Lin, Zhihao
Xue, Naijia
Song, Zhe
Liu, Yi
Zhang, Baorong
Pu, Jiali
author_sort Zheng, Ran
collection PubMed
description BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson’s disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α‑synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α‑synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α‑synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α‑synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02709-w.
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spelling pubmed-98993822023-02-06 ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities Zheng, Ran Yan, Yiqun Dai, Shaobing Ruan, Yang Chen, Ying Hu, Chenjun Lin, Zhihao Xue, Naijia Song, Zhe Liu, Yi Zhang, Baorong Pu, Jiali J Neuroinflammation Research BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson’s disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α‑synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α‑synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α‑synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α‑synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02709-w. BioMed Central 2023-02-05 /pmc/articles/PMC9899382/ /pubmed/36740674 http://dx.doi.org/10.1186/s12974-023-02709-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zheng, Ran
Yan, Yiqun
Dai, Shaobing
Ruan, Yang
Chen, Ying
Hu, Chenjun
Lin, Zhihao
Xue, Naijia
Song, Zhe
Liu, Yi
Zhang, Baorong
Pu, Jiali
ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title_full ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title_fullStr ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title_full_unstemmed ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title_short ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities
title_sort asc specks exacerbate α‑synuclein pathology via amplifying nlrp3 inflammasome activities
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899382/
https://www.ncbi.nlm.nih.gov/pubmed/36740674
http://dx.doi.org/10.1186/s12974-023-02709-w
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