Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration

Evidence garnered from both human autopsy studies and genetic animal models has suggested a potential role for astrocytes in the pathogenesis of amyot rophic lateral sclerosis (ALS). Currently, mutations in the gene encoding C u/Zn superoxide dismutase (SOD1) represent the only known cause of motoneur on loss in the disease, producing 21q linked familial ALS (FALS). To determ ine whether astrocytic dysfunction has a primary role in familial ALS, we h ave generated multiple lines of transgenic mice expressing G86R mutant SOD1 restricted to astrocytes. In GFAP-m SOD1 mice, astrocytes exhibit signific ant hypertrophy and increased GFAP reactivity as the animals mature. Howeve r, GFAP-mutant SOD1 transgenic mice develop normally and do not experience spontaneous motor deficits with increasing age. Histological examination of spinal cord in aged GFAP-mSOD1 mice reveals normal motoneuron and microgli al morphology. These results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that expression of mutant SOD1 restricted to a strocytes is not sufficient to cause motoneuron degeneration in vivo. Expre ssion of mutant SOD1 in other cell types, most likely neurons, is critical for the initiation of disease.