Parkinson's disease (PD) involves an irreversible degeneration of the nigrostriatal pathway. As most cases of PD are sporadic, environmental risk factors may underlie neurodegeneration in dopaminergic neurons. One such factor is 6-hydroxydopamine (6-OHDA), which is widely used as a parkinsonian mimetic. Studies have shown that 6-OHDA generates reactive oxygen species and induces cell stress, the unfolded protein response, and apoptosis. Present findings show that 6-OHDA, but not hydrogen peroxide, MPP+, or rotenone, leads to the rapid formation of high-molecular-weight species of protein disulfide isomerase-associated protein 3 (ERp57) in a dose- and time-dependent fashion. Moreover, ERp57 conjugates are blocked by N-acetylcysteine and glutathione, suggesting that they represent oxidized forms of protein. Surprisingly, conjugates are complexed with DNA, because treatment with DNase reduces their appearance. Subcellular fractionation indicates that both nuclear and mitochondrial DNA are associated with the protein. Finally, toxin-treated ERp57 rapidly forms juxtanuclear aggresome-like structures in dopaminergic cells, suggesting that ERp57 plays an early adaptive response in toxin-mediated stress. Understanding the signaling mechanisms associated with parkinsonian mimetics, as well as their temporal induction, may aid in designing better interventions in models of PD.