Alpha-synuclein/MPP+ mediated activation of NLRP3 inflammasome through microtubule-driven mitochondrial perinuclear transport

Xueping Yang; Huihan Ma; Qingyun Yv; Fanlong Ye; Zhang He; Sheng Chen; Alimu Keram; Wenwei Li; Min Zhu

doi:10.1016/j.bbrc.2022.01.047

Alpha-synuclein/MPP⁺ mediated activation of NLRP3 inflammasome through microtubule-driven mitochondrial perinuclear transport

Biochem Biophys Res Commun. 2022 Feb 26:594:161-167. doi: 10.1016/j.bbrc.2022.01.047. Epub 2022 Jan 19.

Authors

Xueping Yang¹, Huihan Ma¹, Qingyun Yv¹, Fanlong Ye¹, Zhang He¹, Sheng Chen¹, Alimu Keram¹, Wenwei Li², Min Zhu³

Affiliations

¹ Laboratory of Neurophysiology and Neuropathology, Department of Neurology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Institute of Neurology, Institutes of Integrative Medicine, Fudan University, Shanghai, China.
² Laboratory of Neurophysiology and Neuropathology, Department of Neurology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Institute of Neurology, Institutes of Integrative Medicine, Fudan University, Shanghai, China. Electronic address: wenweili2000@aliyun.com.
³ Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Fudan University, Shanghai, China.

PMID: 35085893
DOI: 10.1016/j.bbrc.2022.01.047

Abstract

1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can activate nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome in Parkinson's disease (PD) mice, while 1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridinium ion (MPP⁺), the toxic metabolite of MPTP was not enough to achieve it in vitro. We hypothesized that the accumulation of Alpha-synuclein (α-syn) caused by MPP⁺ can be a priming signal of MPP⁺ mediated NLRP3 activation, and its mechanism was explored. This study demonstrated the α-syn can mediate NLRP3 priming in BV2 cells. It can also act on ERK-p67phox-nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) axis and induce mitochondrial damage. The co-treatment of α-syn/MPP⁺ can cause aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme nicotinamide adenine dinucleotide (NAD⁺), mediate accumulation of ac-α-tubulin, and induce mitochondrial perinuclear aggregation, navigating the co-localization of NLRP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC). This study suggested that α-syn/MPP⁺ mediated NLRP3 inflammasome activation through microtubule-driven mitochondrial perinuclear transport.

Keywords: Alpha-synuclein; MPP(+); Mitochondria; NLRP3 inflammasome; Tubulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus*
Animals
Apoptosis
Cell Line
Inflammasomes / metabolism*
Mice
Microscopy, Confocal
Microscopy, Electron, Transmission
Microtubules / metabolism*
Mitochondria / metabolism*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
Signal Transduction
Sirtuin 2 / metabolism
alpha-Synuclein / metabolism*

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Snca protein, mouse
alpha-Synuclein
SIRT2 protein, human
Sirtuin 2