A proteasomal stress response: Pre-treatment with proteasome inhibitors increases proteasome activity and reduces neuronal vulnerability to oxidative injury

Chul Sang Lee, Lee Y. Tee, Timothy Warmke, Anant Vinjamoori, Ai Li Cai, Anne M. Fagan, B. Joy Snider

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

We report here that exposure to low concentrations of proteasome inhibitors (e.g. 10-100 nM MG-132, 0.1-3 nM epoxomicin or 10-30 nM clasto-lactacystin β-lactone) resulted in an enhancement, rather than an inhibition, of proteasome activity in cultured neocortical neurons. Size-fractionation chromatography confirmed that the enhanced peptide cleavage activity was associated with proteasome-sized complexes. This sub toxic exposure reduced neuronal death caused by subsequent exposure to oxidative stress (100-200 μM H2O2 for 30 min, 24-h exposure to 100 μM paraquat or 7.5 μM menadione), but did not alter vulnerability to excitotoxicity (5-min exposure to 30-100 μM NMDA or 24 exposure to 12 μM NMDA). Sub toxic proteasome inhibitor exposure caused an increase in levels of proteasome core subunit proteins and mRNAs, but not in levels of potentially cytoprotective heat shock proteins (hsp70, hsp90 and hsp40). The neuroprotective effects of proteasome inhibitor pre-treatment were blocked by coapplication of proteasome inhibitors during the oxidative insult. These findings support a model in which sublethal proteasome inhibition induces neurons to increase proteasome activity and promotes resistance to oxidative injury and suggests that enhancement of proteasome activity is a potential therapeutic target for diseases in which oxidative stress has been implicated.

Original languageEnglish
Pages (from-to)996-1006
Number of pages11
JournalJournal of Neurochemistry
Volume91
Issue number4
DOIs
StatePublished - Nov 2004

Keywords

  • Excitotoxicity
  • GFP
  • Gene expression
  • Oxidative injury
  • Proteasome
  • Stress response

Fingerprint Dive into the research topics of 'A proteasomal stress response: Pre-treatment with proteasome inhibitors increases proteasome activity and reduces neuronal vulnerability to oxidative injury'. Together they form a unique fingerprint.

Cite this