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

ABSTRACT: 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-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 Ca²⁺ 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 neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF-?B 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 neuroblastoma cells by increasing Ca²⁺ entry, restoring NF-?B activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca²⁺ entry, which inhibited the binding of NF-?B 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-?B-mediated regulation of TRPC1 expression and autophagy.

SUBMITTER: Sukumaran P 

PROVIDER: S-EPMC5892723 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature