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TOXICOLOGY

Dieldrin Induces Ubiquitin-Proteasome Dysfunction in -Synuclein Overexpressing Dopaminergic Neuronal Cells and Enhances Susceptibility to Apoptotic Cell Death

Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, Iowa

Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of -synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human -synuclein. Overexpression of wild-type -synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0–70 µM) decreased proteasomal activity, and 30 µM dieldrin inhibited activity by more than 60% in -synuclein cells. Confocal microscopic analysis of dieldrin-treated -synuclein cells revealed that -synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The dieldrin-induced proteasomal dysfunction in -synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after dieldrin treatment and that -synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of -synuclein cells to dieldrin-induced apoptosis. Together, our results suggest that increased expression of -synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as dieldrin.

Address correspondence to: Dr. A. G. Kanthasamy, Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, 2008 Veterinary Medicine Building, Iowa State University, Ames, IA 50011-1250. E-mail: akanthas{at}iastate.edu

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