Abstract
BackgroundParkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), resulting in tremor, rigidity, and bradykinesia. Although the etiology is unknown, insight into the disease process comes from the dopamine (DA) derivative, 6-hydroxydopamine (6-OHDA), which produces PD-like symptoms. Studies show that 6-OHDA activates stress pathways, such as the unfolded protein response (UPR), triggers mitochondrial release of cytochrome-c, and activates caspases, such as caspase-3. Because the BH3-only protein, Puma (p53-upregulated mediator of apoptosis), is activated in response to UPR, it is thought to be a link between cell stress and apoptosis.ResultsTo test the hypothesis that Puma serves such a role in 6-OHDA-mediated cell death, we compared the response of dopaminergic neurons from wild-type and Puma-null mice to 6-OHDA. Results indicate that Puma is required for 6-OHDA-induced cell death, in primary dissociated midbrain cultures as well as in vivo. In these cultures, 6-OHDA-induced DNA damage and p53 were required for 6-OHDA-induced cell death. In contrast, while 6-OHDA led to upregulation of UPR markers, loss of ATF3 did not protect against 6-OHDA.ConclusionsTogether, our results indicate that 6-OHDA-induced upregulation of Puma and cell death are independent of UPR. Instead, p53 and DNA damage repair pathways mediate 6-OHDA-induced toxicity.
Highlights
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), resulting in tremor, rigidity, and bradykinesia
Even though Puma mRNA was upregulated by 9 hours after 6-OHDA treatment, Puma protein did not significantly increase until 24 hours (Figure 1E, F). The source of this discrepancy is unclear, it is possible that western blot sensitivity was sufficiently variable as to prevent detection of smaller changes. These results demonstrate that 6-OHDA induces the upregulation of Puma in a ROS-dependent manner, suggesting that Puma plays a role in 6-OHDA-mediated cell death
These results indicate that ATF3 is not required for cell death induced by 6-OHDA and suggest that unfolded protein response (UPR) does not play a direct role in the induction of apoptosis by 6-OHDA
Summary
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), resulting in tremor, rigidity, and bradykinesia. The BH3-only protein, Puma, is activated in response to a variety of death stimuli, including DNA damage, ER stress, and oncogene-mediated hyperproliferation [16,17,18]. Each of these insults induces PUMA expression, resulting in cytochrome-c release from the mitochondria, caspase activation and apoptosis [17,19,20]. Cells deficient in Puma are resistant to ER stress- and DNA damage-induced apoptosis [16,18] These data are consistent with studies suggesting that when UPR pathways are overwhelmed apoptosis is triggered [21,22]. Puma may provide a link between ER stress, UPR and apoptosis
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