title: Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis.
abstract: 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.
authors.affiliation: Genzyme, Framingham, MA 01701-9322, USA. jim.dodge@genzyme.com
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fidler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Tamsett
authors.forename: Channa
authors.initials: C
authors.lastname: Bao
authors.forename: Michelle
authors.initials: M
authors.lastname: Searles
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Taksir
authors.forename: Kuma
authors.initials: K
authors.lastname: Misra
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D006003:Glycogen; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: carbonic anhydrase; electrolyte; glucagon; glycoproteins; motor neuron disease