Coat protein complex II vesicle transport is involved in tri-o-cresyl phosphate-induced delayed neuropathy

TOCP reduces COPII vesicles in the spinal cord and sciatic nerves of adult hens. • TOCP metabolite CBDP inhibits COPII-mediated ER-to-Golgi trafficking in Schwann cells. • TOCP/CBDP-induced COPII transport defects are involved in ER stress (ERS). • ERS inhibitor 4-PBA partially rescues COPII transport defects and neurotoxic injury. Tri- ortho -cresyl phosphate (TOCP) is an organophosphorus compounds (OP) known to induce delayed neurotoxicity, called OP-induced delayed neuropathy (OPIDN), which involves multiple pathological processes, including degeneration and demyelination of long axons within the spinal cord and peripheral nerves. In this study, we employed the Schwann cell line (sNF96.2 cells) and adult hen, the classical model animal for OPIDN study, to investigat e the mechanism of TOCP-induced myelin damage. The results showed that TOCP (750 mg/kg, p.o.) significantly reduced the number of COPII vesicles in the spinal cord and sciatic nerves of hens; on day 2 after the single exposure, the number of vesicles decreased to 27% and 38% of the control group, respectively, while 4-phenylbutyric acid (4-PBA, 150 mg/kg, i.p.), an inhibitor of endoplasmic reticulum (ER) stress restored them to 80% and 75% of the control group, respectively. In sNF96.2 cells, cresyl saligenin phosphate (CBDP), the active metabolite of TOCP, inhibited COPII vesicle transport from the ER to the Golgi apparatus, reducing the transport rate of ManII-SBP-mCherry from 76% to 38% and the relocation rate of GalNAc-T2-GFP in the Golgi apparatus from 91% to 26%. 4-PBA partially reversed the effects (restoring them to 62% and 72%, respectively). These results suggested that TOCP/CBDP impairs COPII vesicle transport at least partially by activating ER stress, and that impaired vesicle transport may be an important mechanism by which TOCP induces neuropathy. Download: Download high-res image (156KB) Download: Download full-size image