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

Xueping Yang1, Huihan Ma1, Qingyun Yv1

  • 1Laboratory 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.

Biochemical and Biophysical Research Communications
|January 27, 2022
PubMed

Insights

Alpha-synuclein accumulation, triggered by MPP+, primes the NLRP3 inflammasome. This process involves mitochondrial damage and microtubule-driven transport, offering insights into Parkinson's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease (PD) models.
  • MPTP metabolite MPP+ alone is insufficient for NLRP3 inflammasome activation in vitro.
  • Alpha-synuclein (α-syn) aggregation is a hallmark of Parkinson's disease.

Purpose of the Study:

  • To investigate the role of α-syn accumulation as a priming signal for MPP+-mediated NLRP3 inflammasome activation.
  • To elucidate the underlying mechanisms of NLRP3 activation in response to α-syn and MPP+.

Main Methods:

  • Utilized BV2 cells to study α-syn mediated NLRP3 priming.
  • Investigated the ERK-p67phox-Nox2 signaling axis.
  • Assessed mitochondrial homeostasis, NAD+ levels, and ac-α-tubulin accumulation.
  • Examined NLRP3 and ASC co-localization and mitochondrial perinuclear aggregation.

Main Results:

  • Demonstrated that α-syn mediates NLRP3 priming in BV2 cells.
  • Identified α-syn's action on the ERK-p67phox-Nox2 axis, leading to mitochondrial damage.
  • Observed that co-treatment with α-syn/MPP+ disrupts mitochondrial homeostasis, reduces NAD+ levels, and causes ac-α-tubulin accumulation.
  • Showcased mitochondrial perinuclear aggregation and co-localization of NLRP3 and ASC.

Conclusions:

  • α-syn acts as a priming signal for MPP+-induced NLRP3 inflammasome activation.
  • MPP+ and α-syn co-treatment induce mitochondrial dysfunction and inflammasome activation via microtubule-dependent mitochondrial perinuclear transport.
Keywords:
Alpha-synucleinMPP(+)MitochondriaNLRP3 inflammasomeTubulin

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