ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury

Although degeneration of lower motor neurons is the most striking abnormali ty in amyotrophic lateral sclerosis (ALS), more subtle alterations may occu r in the brain. Mutations in copper/zinc superoxide dismutase (Cu/Zn-SOD) a re 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 c linical phenotype similar to that of ALS patients. It is now reported that Cu/Zn-SOD mutant mice exhibit increased vulnerability to focal ischemic bra in injury after transient occlusion of the middle cerebral artery. Levels o f glucose and glutamate transport in cerebral cortex synaptic terminals wer e markedly decreased, and levels of membrane lipid peroxidation were increa sed in Cu/Zn-SOD mutant mice compared to nontransgenic mice. These findings demonstrate that mutant Cu/Zn-SOD may endanger brain neurons by a mechanis m involving impairment of glucose and glutamate transporters. Moreover, our data demonstrate a direct adverse effect of the mutant enzyme on synaptic function.