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.