NLRP3 Inflammasome-Mediated Neuroinflammation and Related Mitochondrial Impairment in Parkinson's Disease

Overview

Journal Neurosci Bull

Specialty Neurology

Date 2023 Feb 9

PMID 36757612

Authors

Qiu-Qin Han

Weidong Le

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder caused by the loss of dopamine neurons in the substantia nigra and the formation of Lewy bodies, which are mainly composed of alpha-synuclein fibrils. Alpha-synuclein plays a vital role in the neuroinflammation mediated by the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in PD. A better understanding of the NLRP3 inflammasome-mediated neuroinflammation and the related mitochondrial impairment during PD progression may facilitate the development of promising therapies for PD. This review focuses on the molecular mechanisms underlying NLRP3 inflammasome activation, comprising priming and protein complex assembly, as well as the role of mitochondrial impairment and its subsequent inflammatory effects on the progression of neurodegeneration in PD. In addition, the therapeutic strategies targeting the NLRP3 inflammasome for PD treatment are discussed, including the inhibitors of NLRP3 inflammatory pathways, mitochondria-focused treatments, microRNAs, and other therapeutic compounds.

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References

Wang Y, Gao W, Shi X, Ding J, Liu W, He H . Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017; 547(7661):99-103. DOI: 10.1038/nature22393. View

Voet S, Srinivasan S, Lamkanfi M, van Loo G . Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019; 11(6). PMC: 6554670. DOI: 10.15252/emmm.201810248. View

Cullen S, Kearney C, Clancy D, Martin S . Diverse Activators of the NLRP3 Inflammasome Promote IL-1β Secretion by Triggering Necrosis. Cell Rep. 2015; 11(10):1535-48. DOI: 10.1016/j.celrep.2015.05.003. View

Zhou Y, Lu M, Du R, Qiao C, Jiang C, Zhang K . MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease. Mol Neurodegener. 2016; 11:28. PMC: 4833896. DOI: 10.1186/s13024-016-0094-3. View

Sarkar S, Malovic E, Harishchandra D, Ghaisas S, Panicker N, Charli A . Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease. NPJ Parkinsons Dis. 2017; 3:30. PMC: 5645400. DOI: 10.1038/s41531-017-0032-2. View

Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L . Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One. 2013; 8(1):e55375. PMC: 3561263. DOI: 10.1371/journal.pone.0055375. View

Kim C, Ho D, Suk J, You S, Michael S, Kang J . Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013; 4:1562. PMC: 4089961. DOI: 10.1038/ncomms2534. View

Lee E, Hwang I, Park S, Hong S, Hwang B, Cho Y . MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 2018; 26(2):213-228. PMC: 6329843. DOI: 10.1038/s41418-018-0124-5. View

Litwiniuk A, Baranowska-Bik A, Domanska A, Kalisz M, Bik W . Contribution of Mitochondrial Dysfunction Combined with NLRP3 Inflammasome Activation in Selected Neurodegenerative Diseases. Pharmaceuticals (Basel). 2021; 14(12). PMC: 8703835. DOI: 10.3390/ph14121221. View

10.

Ahmed S, Panda S, Kwatra M, Sahu B, Naidu V . Perillyl Alcohol Attenuates NLRP3 Inflammasome Activation and Rescues Dopaminergic Neurons in Experimental In Vitro and In Vivo Models of Parkinson's Disease. ACS Chem Neurosci. 2021; 13(1):53-68. DOI: 10.1021/acschemneuro.1c00550. View

11.

Mao Z, Liu C, Ji S, Yang Q, Ye H, Han H . The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson's Disease in Rats. Neurochem Res. 2017; 42(4):1104-1115. DOI: 10.1007/s11064-017-2185-0. View

12.

Oberg M, Fabrik I, Fabrikova D, Zehetner N, Hartlova A . The role of innate immunity and inflammation in Parkinson´s disease. Scand J Immunol. 2021; 93(5):e13022. DOI: 10.1111/sji.13022. View

13.

Qin Y, Qiu J, Wang P, Liu J, Zhao Y, Jiang F . Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson's disease. Brain Behav Immun. 2020; 91:324-338. DOI: 10.1016/j.bbi.2020.10.010. View

14.

Prochnicki T, Mangan M, Latz E . Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016; 5. PMC: 4963208. DOI: 10.12688/f1000research.8614.1. View

15.

Zeng R, Luo D, Li H, Zhang Q, Lei S, Chen J . MicroRNA-135b alleviates MPP-mediated Parkinson's disease in in vitro model through suppressing FoxO1-induced NLRP3 inflammasome and pyroptosis. J Clin Neurosci. 2019; 65:125-133. DOI: 10.1016/j.jocn.2019.04.004. View

16.

Pfeiffer R . Non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord. 2015; 22 Suppl 1:S119-22. DOI: 10.1016/j.parkreldis.2015.09.004. View

17.

Sun Q, Wang S, Chen J, Cai H, Huang W, Zhang Y . MicroRNA-190 alleviates neuronal damage and inhibits neuroinflammation via Nlrp3 in MPTP-induced Parkinson's disease mouse model. J Cell Physiol. 2019; 234(12):23379-23387. DOI: 10.1002/jcp.28907. View

18.

Fayyad M, Salim S, Majbour N, Erskine D, Stoops E, Mollenhauer B . Parkinson's disease biomarkers based on α-synuclein. J Neurochem. 2019; 150(5):626-636. DOI: 10.1111/jnc.14809. View

19.

Sun Q, Zhang Y, Wang S, Yang F, Cai H, Xing Y . NEAT1 Decreasing Suppresses Parkinson's Disease Progression via Acting as miR-1301-3p Sponge. J Mol Neurosci. 2020; 71(2):369-378. DOI: 10.1007/s12031-020-01660-2. View

20.

Fan Z, Pan Y, Zhang Z, Yang H, Yu S, Zheng Y . Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson's disease. J Neuroinflammation. 2020; 17(1):11. PMC: 6950934. DOI: 10.1186/s12974-019-1670-6. View