Dopaminergic neurotoxins induce cell death by attenuating NF‐κB‐mediated regulation of TRPC1 expression and autophagy. Issue 3 (3rd January 2018) - Sukumaran, Pramod
Abstract : Alterations in Ca 2 + homeostasis affect neuronal survival. However, the identity of Ca 2 + 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‐phenylpyridium ions (MPP+)/1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP), which mimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store‐mediated Ca 2 + entry. The function of the transient receptor potential canonical (TRPC)‐1 channel was decreased upon exposure to the neurotoxins, followed by a decrease in TRPC1 expression. Similar to neurotoxins, 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 neu‐roblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF‐κB to the TRPC1 promoter, which resulted in a decrease in TRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neu‐roblastoma cells by increasing Ca 2 + entry, restoring NF‐ΚB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca 2 + entry, which inhibited the binding of NF‐κB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.— Sukumaran, P., Sun, Y., Antonson, N., Singh, B. B. Dopaminergic neurotoxins induce cell death by attenuating NF‐κB‐mediated regulation of TRPC1 expression and autophagy. FASEB J. 32, 1640‐1652 (2018). www.fasebj.org