Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and depletion of striatal dopamine (DA), leading to a range of motor symptoms, including resting tremor, rigidity, bradykinesia and postural abnormalities. The neurotoxin (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+), cause dopaminergic cell loss in a variety of animal species and produce symptoms similar to those seen in PD. Our lab has shown that MPP+ activates cell stress pathways, including the unfolded protein response (UPR) in mouse primary mesencephalic cultures. The BH3-only protein, PUMA (p53 upregulated mediator of apoptosis), has been shown to be activated in response to many cellular stresses, including endoplasmic reticulum (ER) stress and UPR, and to induce cell death. Therefore, we hypothesized that PUMA may mediate MPP+ toxicity. To test this hypothesis, we compared the response of primary mesencephalic cultures from wild-type and PUMA deficient (-/-) mice to MPP+. We also utilized cultures from p53 -/- and activating transcription factor 3 (ATF3) -/- mice to further elucidate the pathways involved. These studies revealed that PUMA and p53, but not ATF3, are required for MPP+-induced cell death, suggesting that UPR activation is parallel to the induction of MPP+-induced cell death.