Oxidative stress-triggered unfolded protein response is upstream of intrinsic cell death evoked by parkinsonian mimetics
Article first published online: 17 JUL 2006
Journal of Neurochemistry
Volume 99, Issue 1, pages 54–69, October 2006
How to Cite
Holtz, W. A., Turetzky, J. M., Jong, Y.-J. I. and O'Malley, K. L. (2006), Oxidative stress-triggered unfolded protein response is upstream of intrinsic cell death evoked by parkinsonian mimetics. Journal of Neurochemistry, 99: 54–69. doi: 10.1111/j.1471-4159.2006.04025.x
- Issue published online: 17 JUL 2006
- Article first published online: 17 JUL 2006
- Received January 9, 2006; revised manuscript received May 18, 2006; accepted May 19, 2006.
- Parkinson's disease;
- reactive oxygen species;
- unfolded protein response
Oxidative stress is a key player in a variety of neurodegenerative disorders including Parkinson's disease. Widely used as a parkinsonian mimetic, 6-hydroxydopamine (6-OHDA) generates reactive oxygen species (ROS) as well as coordinated changes in gene transcription associated with the unfolded protein response (UPR) and apoptosis. Whether 6-OHDA-induced UPR activation is dependent on ROS has not yet been determined. The present study used molecular indicators of oxidative stress to place 6-OHDA-generated ROS upstream of the appearance of UPR markers such as activating transcription factor 3 (ATF3) and phosphorylated stress-activated protein kinase (SAPK/JNK) signaling molecules. Antioxidants completely blocked 6-OHDA-mediated UPR activation and rescued cells from toxicity. Moreover, cytochrome c release from mitochondria was observed after the appearance of early UPR markers, suggesting that cellular stress pathways are responsible for its release. Mechanistically, the 6-OHDA-induced UPR was independent of intracellular calcium changes. Rather, evidence of protein oxidation was observed before the expression of UPR markers, suggesting that the rapid accumulation of damaged proteins triggered cell stress/UPR. Taken together, 6-OHDA-mediated cell death in dopaminergic cells proceeds via ROS-dependent UPR up-regulation which leads to an interaction with the intrinsic mitochondrial pathway and downstream caspase activation.