Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism.
The role of the proteasome in neurodegenerative diseases is controversial. On the one hand, there is evidence that a dysfunction of proteasome activity can lead to neurodegeneration but there is also data showing that proteasome inhibition can protect nerve cells from a variety of insults. In an attempt to clarify this issue, we studied the effects of four different proteasome inhibitors in a well characterized model of oxidative stress-induced nerve cell death. Consistent with the hypothesis that proteasome inhibition can be neuroprotective, we found that low concentrations of proteasome inhibitors were able to protect nerve cells from oxidative stress-induced death. Surprisingly, the neuroprotective effects of the proteasome inhibitors appeared to be at least partially mediated by the induction of NF-kappaB since protection was significantly reduced in cells expressing a specific NF-kappaB repressor. The activation of NF-kB by proteasome inhibitors was mediated by IkappaB alpha and IKK and was blocked by antioxidants and inhibitors of mitochondrial reactive oxygen species production. These data suggest that low concentrations of proteasome inhibitors induce a moderate level of mitochondrial oxidative stress which results in the activation of neuroprotective pathways.
Maher
Pamela
P
The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, United States. pmaher@salk.edu
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; D019803:Glutathione Disulfide