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PARP1 promotes NLRP3 activation via blocking TFEB-mediated autophagy in rotenone-induced neurodegeneration

He Zhang1, Zhefan Xie2, Yongming Peng1

  • 1Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China.

Ecotoxicology and Environmental Safety
|February 10, 2023
PubMed

Insights

PARP1 overactivation by the pesticide rotenone impairs autophagy and triggers inflammation, increasing Parkinson's disease risk. Inhibiting PARP1 protects neurons by restoring autophagy and reducing inflammation.

Area of Science:

  • Neuroscience
  • Toxicology
  • Molecular Biology

Background:

  • Rotenone pesticide exposure is linked to dopaminergic neuron loss and Parkinson's disease (PD).
  • The roles of PARP1, neuroinflammation, and autophagy dysfunction in rotenone-induced neurodegeneration are not fully understood.

Purpose of the Study:

  • To investigate the role of PARP1 in rotenone-induced neuroinflammation and autophagy dysfunction.
  • To explore the potential of PARP1 inhibition as a therapeutic strategy for rotenone-induced neurodegeneration.

Main Methods:

  • Utilized rotenone models to induce neurodegeneration.
  • Assessed the impact of PARP1 activation and inhibition on autophagy and NLRP3-mediated inflammation.
  • Investigated the interaction between PARP1 and TFEB (Transcription Factor EB).

Main Results:

  • Rotenone exposure led to PARP1 overactivation, causing autophagy dysfunction and NLRP3-driven inflammation.
  • PARP1 inhibition reduced NLRP3 inflammation, an effect dependent on TFEB.
  • PARP1 poly(ADP-ribosyl)ated TFEB, inhibiting autophagy and promoting neuroinflammation.
  • PARP1 inhibition rescued rotenone-induced dopaminergic neuron loss.

Conclusions:

  • PARP1 exacerbates rotenone-induced neurodegeneration by inhibiting autophagy via TFEB poly(ADP-ribosyl)ation and promoting NLRP3 inflammation.
  • Targeting the PARP1-TFEB-NLRP3 signaling pathway presents a promising therapeutic avenue for Parkinson's disease and related neurodegenerative conditions.
Keywords:
AutophagyNLRP3PARP1RotenoneTFEB

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