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Asparagine endopeptidase inhibitor protects against fenpropathrin-induced neurodegeneration via suppressing α-synuclein aggregation and neuroinflammation.

Abstract
Exposure to fenpropathrin (Fen), one of the most widely used pyrethroid pesticides, has been reported to increase the incidence of Parkinson's disease (PD). However, the molecular mechanisms underlying Fen-induced Parkinsonism remain unknown. Here we investigated the role of the lysosomal protease asparagine endopeptidase (AEP) in Fen-induced neurodegeneration and tested the protective effect of an AEP inhibitor Compound #11 (CP11). Fen induced AEP activation, α-synuclein aggregation, and dopaminergic neuronal degeneration both in vitro and in vivo. CP11 alleviated Fen-induced cell injury in cultured SH-SY5Y cells and A53T α-synuclein transgenic mice. CP11 protected SH-SY5Y cells against Fen-induced toxicity and decreased α-synuclein aggregation in HEK293 cells stably transfected with α-synuclein. In Fen-treated mice, CP11 attenuated the degeneration of dopaminergic neurons and reduced neuroinflammation. Our findings demonstrate that neurodegeneration in Fen-treated models might be attributed to the activation of AEP. AEP might be a novel therapeutic target in PD induced by Fen and other environmental factors.
AuthorsTing Yu, Fang Wan, Chaoyang Liu, Xingyu Zhang, Zehua Liu, Jichun Zhang, Jing Xiong, Tao Wang, Zhentao Zhang
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 888 Pg. 173586 (Dec 05 2020) ISSN: 1879-0712 [Electronic] Netherlands
PMID32971086 (Publication Type: Journal Article)
CopyrightCopyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Neuroprotective Agents
  • Protease Inhibitors
  • Protein Aggregates
  • Pyrethrins
  • alpha-Synuclein
  • fenpropathrin
  • Cysteine Endopeptidases
  • asparaginylendopeptidase
Topics
  • Animals
  • Cell Line, Tumor
  • Cysteine Endopeptidases (metabolism)
  • Dose-Response Relationship, Drug
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neurodegenerative Diseases (chemically induced, metabolism, prevention & control)
  • Neuroprotective Agents (pharmacology, therapeutic use)
  • Protease Inhibitors (pharmacology, therapeutic use)
  • Protein Aggregates (drug effects, physiology)
  • Pyrethrins (toxicity)
  • alpha-Synuclein (antagonists & inhibitors, metabolism)

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