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Chronic Microcystin-LR-Induced α-Synuclein Promotes Neuroinflammation Through Activation of the NLRP3 Inflammasome in Microglia

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Abstract

Microcystin-LR (MC-LR) has been confirmed to cause blood–brain barrier disruption and enter the brain tissue, resulting in non-negligible toxic effects. However, the neurotoxicity of MC-LR is mainly unknown. This study revealed that MC-LR disrupted the function of the ubiquitin–proteasome system in neurons, which inhibited the degradation of α-synuclein (α-syn), leading to its release from neurons for transport into microglia. α-Syn is the main component of Lewy bodies, which has been identified as one of the main pathological features of Parkinson’s disease (PD). In vitro, we observed that α-syn mediated by MC-LR activated HMC3 cells and polarized them towards M1 type. In addition, we confirmed that α-syn was transported into HMC3 cells through TLR4 receptors and activated the NLRP3 inflammasome, which in turn enhanced the maturation and release of IL-18 and IL-1β. In the mouse models of chronic MC-LR exposure, a large number of inflammatory factors (IL-6, IL-1β, and TNF-α) were deposited in brain tissue, and activation of NLRP3 in microglia was also observed in the midbrain. Collectively, MC-LR exposure promoted the pathological spread of α-syn from cell to cell, activated NLRP3 inflammasome in microglia, and generated neuroinflammation, in which the TLR4 receptor played a substantial effect.

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The datasets used and/or analyzed in this article are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (31870492, 31901182, 31670519, and 31971517), the Natural Science Foundation of Jiangsu Province of China (BK20190316), and Fundamental Research Funds for the Central Universities (0214–14380438 and 0214–14380471).

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Authors and Affiliations

  1. Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China

    Minghao Yan, Haibo Jin, Chun Pan & Xiaodong Han

  2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China

    Minghao Yan, Haibo Jin, Chun Pan & Xiaodong Han

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  1. Minghao Yan
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Minghao Yan—writing of the first draft, manuscript preparation. Haibo Jin—writing of the first draft, review, and critique. Chun Pan—writing of the first draft, review, and critique. Xiaodong Han—review and critique.

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Correspondence to Xiaodong Han.

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All animal procedures were performed humanely and approved by the Nanjing University Animal Care and Use Committee under animal protocol number SYXK (Su) 2009–0017.

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Yan, M., Jin, H., Pan, C. et al. Chronic Microcystin-LR-Induced α-Synuclein Promotes Neuroinflammation Through Activation of the NLRP3 Inflammasome in Microglia. Mol Neurobiol 60, 884–900 (2023). https://doi.org/10.1007/s12035-022-03134-5

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