Dopaminergic neurotoxins induce cell death by attenuating NF-κB-mediated regulation of TRPC1 expression and autophagy

Alterations in Ca²⁺ homeostasis affect neuronal survival. However, the identity of Ca²⁺ channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridiumions (MPP⁺)/1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), whichmimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca²⁺ entry. The function of the transient receptor potential canonical (TRPC)-1 channel wasdecreaseduponexposure to the neurotoxins, followedby a decrease inTRPC1expression.Similar toneurotoxins, samples from patients with PD exhibited attenuated TRPC1 expression, which was accompanied by a decrease in autophagic markers and a subsequent increase in apoptosis markers. Furthermore, exposure to neurotoxins attenuated PKC phosphorylation, decreased expression of autophagic markers, and increased apoptosis in SHSY-5Y neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF-κBto theTRPC1 promoter, which resulted in a decrease inTRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neuroblastoma cells by increasing Ca²⁺ entry, restoring NF-kB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca²⁺ entry, which inhibited the binding of NF-κB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.