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.
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Authors | Ting Yu, Fang Wan, Chaoyang Liu, Xingyu Zhang, Zehua Liu, Jichun Zhang, Jing Xiong, Tao Wang, Zhentao Zhang |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 888
Pg. 173586
(Dec 05 2020)
ISSN: 1879-0712 [Electronic] Netherlands |
PMID | 32971086
(Publication Type: Journal Article)
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Copyright | Copyright © 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
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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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