Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase

Yael Mali, Nava Zisapels*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Protein interactions of the Amyotrophic Lateral Sclerosis (ALS)-linked copper-zinc superoxide dismutase (hSOD1) G93A mutation were studied using a fluorescence resonance energy transfer (FRET) based screening system. The FRET results confirmed by pull-down immunoprecipitation indicated "gain-of-interaction" of the G93A-hSOD1 mutant with cytosolic malate dehydrogenase (cytMDH)-a key enzyme in the malate-aspartate shuttle which is vital to neurons. Furthermore, cytMDH mRNA expression was upregulated in G93A-hSOD1 expressing cells but endogenous cytMDH enzymatic activity was not enhanced, not even with exogenously added-on enzyme. Consistent with inhibition of the malate-aspartate shuttle, G93A-hSOD1 had lower malate and higher lactate levels compared to non-induced or Wild-Type-hSOD1 expressing cells. Mitochondrial NADH/NAD+ ratio is also elevated. Malate-aspartate shuttle dysfunction may explain the damage to neurons and the vulnerability to impairments of glycolytic pathways in ALS and provide a new target for the development of potential therapies.

Original languageEnglish
Pages (from-to)133-141
Number of pages9
JournalNeurobiology of Disease
Issue number1
StatePublished - Oct 2008


  • ALS
  • Amyotrophic Lateral Sclerosis
  • FRET
  • Malate dehydrogenase
  • Neurons
  • Protein interactions
  • SOD1


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