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Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.

Original publication

DOI

10.1007/s12035-015-9165-7

Type

Journal article

Journal

Molecular neurobiology

Publication Date

05/2016

Volume

53

Pages

2222 - 2240

Addresses

Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, South Kensington, London, SW7 2AZ, UK.

Keywords

Cell Line, Animals, Humans, Mice, Amyotrophic Lateral Sclerosis, Lactates, Pyruvic Acid, Superoxide Dismutase, Protein-Serine-Threonine Kinases, Glucose, Amino Acids, Alanine, Glutamine, Culture Media, Serum-Free, Cell Death, Aerobiosis, Glycolysis, Models, Biological, Mutant Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Caspase 3, Caspase 7, Metabolomics, Metabolome, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha