Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease.
Transgenic mice expressing high levels of familial amyotrophic lateral sclerosis (FALS)-associated mutant superoxide dismutase 1 (SOD1) under the control of a human SOD1 minigene (hMg) accumulate mutant protein ubiquitously and develop motoneuron disease. However, restricted expression of SOD1 mutants in neurons apparently does not cause motor impairments in mice. Here, we investigated the possible pathogenic roles of mutant SOD1 accumulation in motoneurons. First, we used a Thy1 expression cassette to drive high constitutive expression of transgene in postnatal mouse neurons, including upper and lower motoneurons. Second, we expressed human (h) SOD1(G93A) and hSOD1(G85R) as transgenes (i.e., two SOD1 mutants with aggressive pathogenic properties in inducing FALS). Third, in addition to clinical signs of disease, we monitored early signs of disease onset and pathogenesis, including muscle innervation, astrogliosis in the spinal cord, and accumulation of ubiquitinated deposits in motoneurons and astrocytes. We report that high-level expression and accumulation of the mutant proteins in neurons failed to produce any detectable sign of pathology or disease in these transgenic mice. Crossing hMg-SOD1(G93A) mice (Gurney et al., 1994) with Thy1-SOD1(G93A) mice produced double-transgenic mice with spinal cord SOD1(G93A) levels that were approximately twofold higher than in the hMg-SOD1(G93A) single transgenics but did not affect the onset or progression of pathology or motoneuron disease. The accumulation of mutant SOD1 in postnatal motoneurons is thus not sufficient and probably also not critical to induce or accelerate motoneuron disease in FALS mice. The pathogenic process in FALS may involve non-neuronal cells, and selective vulnerability of motoneurons to this process may lead to motoneuron pathology and disease.
Lino
Maria Maddalena
MM
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, CH-4058 Basel, Switzerland.
Schneider
Corinna
C
Caroni
Pico
P
D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D018450:Disease Progression; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D018800:Thy-1 Antigens / Q000235:genetics
C000606290:SOD1 protein, human; D018800:Thy-1 Antigens; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1