Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote pkcδ-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model

Hariharan Saminathan, Arunkumar Asaithambi, Vellareddy Anantharam, Anumantha G. Kanthasamy, Arthi Kanthasamy

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Oxidative stress and apoptosis are two key pathophysiological mechanisms underlying dopaminergic degeneration in Parkinson's disease (PD). Recently, we identified that proteolytic activation of protein kinase C-delta (PKCδ), a member of the novel PKC family, contributes to oxidative stress-induced dopaminergic degeneration and that phosphorylation of tyrosine residue 311 (tyr311) on PKCδ is a key event preceding the PKCδ proteolytic activation during oxidative damage. Herein, we report that a non-receptor tyrosine kinase Fyn is significantly expressed in a dopaminergic neuronal N27 cell model. Exposure of N27 cells to the dopaminergic toxicant dieldrin (60 μM) rapidly activated Fyn kinase, PKCδ-tyr311 phosphorylation and proteolytic cleavage. Fyn kinase activation precedes the caspase-3-mediated proteolytic activation of PKCδ. Pre-treatment with p60-tyrosine-specific kinase inhibitor (TSKI) almost completely attenuated dieldrin-induced phosphorylation of PKCδ-tyr311 and its proteolytic activation. Additionally, TSKI almost completely blocked dieldrin-induced apoptotic cell death. To further confirm Fyn's role in the pro-apoptotic function of PKCδ, we adopted the RNAi approach. siRNA-mediated knockdown of Fyn kinase also effectively attenuated dieldrin-induced phosphorylation of PKCδ-tyr311, caspase-3-mediated PKCδ proteolytic cleavage, and DNA fragmentation, suggesting that Fyn kinase regulates the pro-apoptotic function of PKCδ. Collectively, these results demonstrate for the first time that Fyn kinase is a pro-apoptotic kinase that regulates upstream signaling of the PKCδ-mediated apoptotic cell death pathway in neurotoxicity models of pesticide exposure.

Original languageEnglish
Pages (from-to)567-577
Number of pages11
JournalNeuroToxicology
Volume32
Issue number5
DOIs
Publication statusPublished - Oct 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Kinases
  • Neurodegeneration
  • Oxidative stress
  • Pesticides

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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