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.