Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis

Missense mutations in the gene encoding copper zinc superoxide dismutase (S OD1) have been found to cause one form of familial amyotrophic lateral scle rosis (FALS). Although the exact mechanism of disease is unknown, abnormali ties in the ability of mutant SOD1 to bind zinc or copper ions may be cruci al in the pathogenesis of disease. Because members of the metallothionein ( MT) family of zinc and copper binding proteins function as important cellul ar regulators of metal ion bioavailability in the central nervous system, w e used in situ hybridization and immunohistochemistry to study the expressi on pattern of these molecules in a transgenic mouse model of familial ALS. In adult wild-type mouse spinal cord, expression of MT-I and MT-II is restr icted to ependymal cells and a subset of astrocytes located in white matter tracts, while MT-III synthesis is limited to neurons within gray matter. C ompared to wild-type littermates, transgenic mice carrying the G93A SOD1 mu tation demonstrate markedly increased expression of MT-I and MT-II within a strocytes in both white and gray matter as weakness develops. MT-III synthe sis in neurons is also greatly upregulated as G93A SOD1 animals age, with g lial cell expression of MT-III evident by later stages of the disease. Chan ges in MT expression occur before the onset of motor deficits or significan t motor neuron pathology in G93A SOD1 mice and remarkably extend beyond ven tral horn populations of neurons and glia. These results are consistent wit h the hypothesis that metallothioneins may serve an early and important pro tective function in FALS. (C) 2000 Academic Press.