Inhibition of mitochondrial function and the subsequent generation of oxidative stress are strongly suggested to underlie MPTP/MPP+-induced neurotoxicity, which has been used extensively as a model for Parkinson disease. In the present study we have examined the hypothesis that MPP+ targets the endoplasmic reticulum. Because rabbits possess more genetic similarities to primates than to rodents we have selected this animal model system for our MPP+ neurotoxicity studies. MPP+ was administered directly into the brain of New Zealand white rabbits via the intracisternal route, and the effects on tissue from the substantia nigra were examined. Here we demonstrate that MPP+ in a dose-dependent manner induces the loss of tyrosine hydroxylase activity, oxidative DNA damage, and activation of the endoplasmic reticulum stress response. The endoplasmic reticulum response, mediated by activation of ATF-6 and NF-κB, leads to activation of gadd 153. These effects correlate with the activation of caspase-3 and of c-Jun N-terminal kinase (JNK) kinase. We propose that pharmacological agents that inhibit the perturbation of endoplasmic reticulum function or the activation of JNK may represent a potential therapeutic approach for the prevention of neurotoxin-induced Parkinson disease.