A novel oxidative stress dependent apoptotic pathway in pesticide‐induced dopaminergic degeneration in PD models

Abstract

Emerging epidemiological and case control studies suggest that environmental factors especially pesticides are dominant risk factors in the etiology of idiopathic Parkinson's disease (PD). In the present study, we characterized oxidative stress dependent cellular events by exposing rat mesencephalic dopaminergic cell line (N27) and PC 12 cells to dieldrin (a potential environmental risk factor for development of PD). Exposure of dieldrin (30–200 μm) resulted in a rapid increase in generation of reactive oxygen species within 30 min and was followed by release of mitochondrial cytochrome‐c into cytoplasm. Cytochrome‐c then activated a proapoptotic cysteine protease, caspase‐3 in a time‐ and dose‐dependent manner. Interestingly, we also found that dieldrin exposure induces a time‐ and dose‐dependent proteolytic cleavage of native protein kinase Cδ (PKCδ, 74 kDa) to yield 41‐kDa catalytically active and 38‐kDa regulatory fragments. Pretreatment with caspase inhibitors blocked dieldrin‐induced proteolytic cleavage of PKCδ, indicating that cleavage is mediated by caspase‐3. Attenuation of ROS generation, caspase‐3 activation or overexpression of mutant PKCδK376R (dominant negative) almost completely suppressed dieldrin‐induced DNA fragmentation. We also found that dieldrin exposure activates the redox sensitive transcription factor NF‐kB through PKCδ dependent manner. Together, these data demonstrate that caspase‐3 dependent proteolytic activation of PKCδ plays a key role in oxidative stress‐mediated apoptosis in dopaminergic cells following exposure to an environmental neurotoxic agent.Acknowledgements: Supported in part by ES 10586.