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Viability Assays for Cells in Culture
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Viability Assays for Cells in Culture

Published on: January 20, 2014

Adaptation to chronic MG132 reduces oxidative toxicity by a CuZnSOD-dependent mechanism

Rehana K Leak1, Michael J Zigmond, Anthony K F Liou

  • 1Department of Neurology, Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. leakrk@upmc.edu

Journal of Neurochemistry
|May 10, 2008
PubMed

Insights

Cells adapt to chronic stress by increasing antioxidant proteins like copper-zinc superoxide dismutase (CuZnSOD), offering protection even with glutathione (GSH) depletion.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Biochemistry

Background:

  • Cells face chronic stress, necessitating adaptive mechanisms for survival.
  • Proteasome inhibition is a model for inducing chronic cellular stress.
  • Glutathione (GSH) and antioxidant enzymes play roles in cellular defense.

Purpose of the Study:

  • To investigate cellular adaptation to chronic proteasome inhibition.
  • To determine the role of antioxidant proteins in stress adaptation.
  • To elucidate the mechanism of protection against neurotoxins.

Main Methods:

  • PC12 cells were chronically exposed to the proteasome inhibitor MG132.
  • Cellular protection was assessed against 6-hydroxydopamine (6-OHDA) and high-dose MG132.
  • Levels and activity of antioxidant enzymes (SOD, catalase) and GSH were measured.
  • RNA interference (siRNA) was used to reduce copper-zinc superoxide dismutase (CuZnSOD) levels.

Main Results:

  • Chronic MG132 treatment induced slow-developing, sustained protection against 6-OHDA and higher MG132 doses.
  • MG132 treatment increased levels of antioxidant proteins (CuZnSOD, MnSOD, catalase) and heat-shock protein 70.
  • CuZnSOD enzyme activity increased, while MnSOD activity did not change.
  • Glutathione (GSH) levels remained unchanged, and buthionine sulfoximine-induced GSH depletion did not affect MG132 protection.
  • siRNA-mediated knockdown of CuZnSOD attenuated the protective effect against 6-OHDA.

Conclusions:

  • Dopaminergic cells adapt to chronic proteasome inhibition by upregulating endogenous antioxidant proteins, notably CuZnSOD.
  • This adaptive response confers significant protection against neurotoxins and further proteasome inhibition.
  • The observed protection is mediated, at least in part, by enhanced CuZnSOD activity and functions independently of GSH levels.

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