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Cell death mechanisms in ALS

D E Bredesen1, M Wiedau-Pazos, J J Goto

  • 1Program on Aging, Burnham Institute, La Jolla, CA 92037, USA.

Neurology
|October 1, 1996
PubMed
Summary
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Familial ALS mutations in copper-zinc superoxide dismutase (CuZnSOD) enhance peroxidase activity. This enhanced activity, not normal enzyme function, may drive neurodegeneration in familial ALS (FALS).

Area of Science:

  • Biochemistry
  • Neuroscience
  • Genetics

Background:

  • Familial ALS (FALS) is linked to dominant, gain-of-function mutations in copper-zinc superoxide dismutase (CuZnSOD).
  • The specific gain-of-function mechanism remains unidentified.
  • CuZnSOD possesses both superoxide dismutase and peroxidase activities.

Purpose of the Study:

  • To investigate the functional changes in FALS-associated CuZnSOD mutants.
  • To determine if enhanced peroxidase activity contributes to FALS pathogenesis.

Main Methods:

  • Electron paramagnetic resonance (EPR) with spin trapping (DMPO) to measure enzyme activity.
  • Assessing peroxidase activity of wild-type and mutant CuZnSOD (A4V, G93A).
  • Testing the effect of copper chelators (diethyldithiocarbamate, penicillamine) on mutant activity and neural survival in cell culture.

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Main Results:

  • Mutant CuZnSOD (A4V, G93A) retained superoxide dismutase activity but showed significantly enhanced copper-dependent peroxidase activity compared to wild-type.
  • Copper chelators inhibited the enhanced peroxidase activity of mutants but not wild-type enzyme.
  • These chelators promoted neural survival in an ALS cell model, without affecting cells with wild-type CuZnSOD.

Conclusions:

  • FALS-associated CuZnSOD mutants exhibit enhanced, copper-dependent peroxidase activity.
  • This aberrant peroxidase activity, rather than normal CuZnSOD function, is implicated in initiating FALS neuropathology.
  • Targeting this enhanced peroxidase activity may offer a therapeutic strategy for FALS.