Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 26; pp. 10812 - 10817
• Main Authors: Dodge, James C., Treleaven, Christopher M., Fidler, Jonathan A., Tamsett, Thomas J., Bao, Channa, Searles, Michelle, Taksir, Tatyana V., Misra, Kuma, Sidman, Richard L., Cheng, Seng H., Shihabuddin, Lamya S.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences 25.06.2013; National Acad Sciences
• Subjects: Acidosis; Acidosis - etiology; Acidosis - genetics; Acidosis - metabolism; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - etiology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Biological and medical sciences; Biological Sciences; Central nervous system; Disease course; Disease Models, Animal; Disease Progression; Fundamental and applied biological sciences. Psychology; Glucose; Glycogen; Glycogen - metabolism; Humans; Metabolic diseases; Mice; Mice, Transgenic; Motor neurons; Mutation; Pathogenesis; Rodents; Spinal cord; Spinal cord diseases; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Tissues; Vertebrates: nervous system and sense organs; Pancreatic hormone; Nervous system diseases; Glucagon; Disease; Enzyme; Pathogenesis; Lateral; Glycoprotein; Motor neuron disease; Amyotrophic lateral sclerosis; Lyases; glycoproteins; Metabolism; Electrolyte; carbonic anhydrase; Degenerative disease; Carbonate dehydratase; Carbon-oxygen lyases; Spinal cord disease; Hydro-lyases; glucagon; motor neuron disease; electrolyte
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1308421110

Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H ⁺ concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.