TY - JOUR
T1 - 6-OHDA generated ROS induces DNA damage and p53- and PUMA-dependent cell death
AU - Bernstein, Alison I.
AU - Garrison, Sean P.
AU - Zambetti, Gerard P.
AU - O'Malley, Karen L.
N1 - Funding Information:
We thank Drs. Tsonwin Hai (Ohio State University), and Helen Pwinica-Worms (Washington University School of Medicine) for providing us with the ATF3 and p53 mice. We also thank Steve Harmon and Lynn White for technical assistance. All images were acquired at the Bakewell Neuroimaging Facility, which is supported by National Institutes of Health Neuroscience Blueprint Core Grant NS057105 to Washington University and the Bakewell Family Foundation. Stereotactic injections were performed at the Washington University Hope Center for Neurological Disorders Animal Models Core (partially supported by NIH NS 032636). This work was supported by National Institutes of Health grant NS39084 and MH45330.
PY - 2011
Y1 - 2011
N2 - Background. Parkinson'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. Results. To 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. Conclusions. Together, 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.
AB - Background. Parkinson'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. Results. To 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. Conclusions. Together, 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.
UR - http://www.scopus.com/inward/record.url?scp=78650924736&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-6-2
DO - 10.1186/1750-1326-6-2
M3 - Article
C2 - 21211034
AN - SCOPUS:78650924736
VL - 6
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 2
ER -