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

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 (alpha-syn) caused by MPP+ can be a priming signal of MPP+ mediated NLRP3 activation, and its mechanism was explored. This study demonstrated the alpha-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 alpha-syn/MPP+ can cause aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme nicotinamide adenine dinucleotide (NAD(+)), mediate accumulation of ac-alpha-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 alpha-syn/MPP+ mediated NLRP3 inflammasome activation through microtubuledriven mitochondrial perinuclear transport. (C) 2022 Published by Elsevier Inc.

Automated summary

This study explores the mechanism of NLRP3 inflammasome activation mediated by alpha-synuclein/MPP+. It demonstrates that alpha-synuclein can prime NLRP3 in BV2 cells and induce mitochondrial damage through the ERK-p67phox-Nox2 axis. The co-treatment of alpha-synuclein/MPP+ disrupts mitochondrial homeostasis, decreases NAD(+) concentration, and causes the accumulation of ac-alpha-tubulin, leading to mitochondrial perinuclear aggregation and the co-localization of NLRP3 and ASC.