Adaptation to G93Asuperoxide dismutase 1 in a motor neuron cell line model of amyotrophic lateral sclerosis: The role of glutathione

Silvia Tartari, Giuseppina D'Alessandro, Elisabetta Babetto, Milena Rizzardini, Laura Conforti, Lavinia Cantoni

Research output: Contribution to journalArticle

Abstract

Motor neuron degeneration in amyotrophic lateral sclerosis involves oxidative damage. Glutathione (GSH) is critical as an antioxidant and a redox modulator. We used a motor neuronal cell line (NSC-34) to investigate whether wild-type and familial amyotrophic lateral sclerosis-linked G93A mutant Cu,Zn superoxide dismutase (wt/G93ASOD1) modified the GSH pool and glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis. We studied the effect of various G93ASOD1 levels and exposure times. Mutant Cu,Zn superoxide dismutase induced an adaptive process involving the upregulation of GSH synthesis, even at very low expression levels. However, cells with a high level of G93ASOD1 cultured for 10 weeks showed GSH depletion and a decrease in expression of the modulatory subunit of GCL. These cells also had lower levels of GSH and GCL activity was not induced after treatment with the pro-oxidant tert-butylhydroquinone. Cells with a low level of G93ASOD1 maintained higher GSH levels and GCL activity, showing that the exposure time and the level of the mutant protein modulate GSH synthesis. We conclude that failure of the regulation of the GSH pathway caused by G93ASOD1 may contribute to motor neuron vulnerability and we identify this pathway as a target for therapeutic intervention.

Original languageEnglish
Pages (from-to)2861-2874
Number of pages14
JournalFEBS Journal
Volume276
Issue number10
DOIs
Publication statusPublished - May 2009

Keywords

  • Amyotrophic lateral sclerosis
  • Cu,Zn superoxide dismutase
  • Glutamate cysteine ligase
  • Glutathione
  • Motor neuron

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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