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Superoxide dismutase and the death of motoneurons in ALS

J S Beckman1, A G Estévez, J P Crow

  • 1Linus Pauling Institute, and Dept of Biochemistry and Biophysics, Oregon State University, Corvallis 97331, USA. joe.beckman@orst.edu

Trends in Neurosciences
|March 8, 2002
PubMed

Insights

Zinc deficiency in Cu-Zn superoxide dismutase (SOD) causes motoneuron death in ALS. This finding suggests targeting Zn-deficient SOD could be a therapeutic strategy for all forms of amyotrophic lateral sclerosis (ALS).

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motoneuron loss.
  • Mutations in Cu-Zn superoxide dismutase (SOD) are a known cause of ALS, affecting 2-3% of patients.
  • These mutations compromise SOD's structural integrity and reduce its zinc (Zn) binding affinity.

Purpose of the Study:

  • To investigate the role of Zn-deficient SOD in motoneuron apoptosis.
  • To explore whether Zn deficiency in wild-type SOD contributes to ALS pathogenesis.
  • To identify Zn-deficient SOD as a potential therapeutic target for all ALS cases.

Main Methods:

  • Analysis of SOD structure and Zn binding affinity in ALS-associated mutations.
  • Induction of Zn deficiency in both mutant and wild-type SOD.
  • Assessment of motoneuron apoptosis in response to Zn-deficient SOD.

Main Results:

  • Zn-deficient SOD, regardless of mutation status, induces motoneuron apoptosis.
  • The mechanism involves peroxynitrite formation.
  • Zn-deficient wild-type SOD exhibits toxicity comparable to Zn-deficient mutant SOD.

Conclusions:

  • Loss of Zn from SOD is a critical factor in motoneuron degeneration in ALS.
  • Zn-deficient SOD is implicated in both familial and sporadic ALS cases.
  • Targeting Zn-deficient SOD presents a promising therapeutic avenue for all forms of ALS.

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