Abstract
The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H(2)O(2) in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamineand H(2)O(2)-induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogen-activated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.
Highlights
Parkinson disease (PD)2 is characterized by the selective loss of dopaminergic neurons and by the appearance of Lewy bodies in the midbrain
The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis
6-OHDA- and H2O2-induced Cytotoxicity Is Blocked by the Elevation of Intracellular Glutathione—To clarify the contribution of intracellular glutathione to reactive oxygen species (ROS) suppression, we examined the effect of N-acetyl-L-cysteine (NAC), which is a precursor of glutathione and elevates glutathione contents [12]
Summary
The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. We investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation. In the midbrain of patients with PD, the activities of glutathione peroxidase and catalase were reduced, and the amount of glutathione was decreased (9 –11) These observations suggested that antioxidant defense systems are collapsed in the dopaminergic neurons of patients with this disease. We focused on the antioxidant effect of glutathione and investigated the effect of proteasome inhibition on oxidative stressinduced cytotoxicity in differentiated and non-differentiated PC12 cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
