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

Pramod Sukumaran, Yuyang Sun, Neil Antonson, Brij B. Singh

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)1640-1652
Number of pages13
JournalFASEB Journal
Volume32
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • Apoptosis
  • Calcium
  • Calcium channels
  • PD
  • SOCE

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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