Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1

Cytosolic Cu/Zn superoxide dismutase (SOD1) is a ubiquitous small cytosolic metalloenzyme that catalyzes the conversion of superoxide anion to hydroge n peroxide (H2O2). Mutations in the SOD1 gene cause a familial form of amyo trophic lateral sclerosis (fALS). The mechanism by which mutant SOD1s cause s ALS is not understood. Transgenic mice expressing multiple copies of fALS -mutant SOD1s develop an ALS-like motoneuron disease resembling ALS. Here w e report that transgenic mice expressing a high concentration of wild-type human SOD1 (hSOD1(WT)) develop an away of neurodegenerative changes consist ing of (1) swelling and vacuolization of mitochondria, predominantly in axo ns in the spinal cord, brain stem, and subiculum; (2) axonal degeneration i n a number of long fiber tracts, predominantly the spinocerebellar tracts; and (3) at 2 years of age, a moderate loss of spinal motoneurons. Parallel to the development of neurodegenerative changes, hSOD1(WT) mice also develo p mild motor abnormalities. Interestingly, mitochondrial vacuolization was associated with accumulation of hSOD1 immunoreactivity, suggesting that the development of mitochondrial pathology is associated with disturbed SOD1 t urnover. In this study we also crossed hSOD1(WT) mice with a line of fALS-m utant SOD1 mice (hSOD1(G93A)) to generate "double" transgenic mice that exp ress high levels of both wild-type and G93A mutant hSOD1. The "double" tran sgenic mice show accelerated motoneuron death, earlier onset of paresis, an d earlier death as compared with hSOD1(G93A) littermates. Thus in vivo expr ession of high levels of wild-type hSOD1 is not only harmful to neurons in itself, but also increases or facilitates the deleterious action of a fALS- mutant SOD1. Our data indicate Bat it is important for motoneurons to contr ol the SOD1 concentration throughout their processes, acid that events that lead to improper synthesis, transport, or breakdown of SOD1 causing its ac cumulation are potentially dangerous. (C) 2000 Academic Press.