title: ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury.
abstract: Although degeneration of lower motor neurons is the most striking abnormality in amyotrophic lateral sclerosis (ALS), more subtle alterations may occur in the brain. Mutations in copper/zinc superoxide dismutase (Cu/Zn-SOD) are responsible for some cases of inherited ALS, and expression of mutant Cu/Zn-SOD in transgenic mice results in progressive motor neuron loss and a clinical phenotype similar to that of ALS patients. It is now reported that Cu/Zn-SOD mutant mice exhibit increased vulnerability to focal ischemic brain injury after transient occlusion of the middle cerebral artery. Levels of glucose and glutamate transport in cerebral cortex synaptic terminals were markedly decreased, and levels of membrane lipid peroxidation were increased in Cu/Zn-SOD mutant mice compared to nontransgenic mice. These findings demonstrate that mutant Cu/Zn-SOD may endanger brain neurons by a mechanism involving impairment of glucose and glutamate transporters. Moreover, our data demonstrate a direct adverse effect of the mutant enzyme on synaptic function.
authors.affiliation: Sanders-Brown Research Center on Aging, University of Kentucky, Lexington, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
authors.forename: M S
authors.initials: MS
authors.lastname: Kindy
authors.forename: I
authors.initials: I
authors.lastname: Kruman
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D013569:Synapses / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D013482:Superoxide Dismutase; D005947:Glucose