Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy

Objective: To characterize the motor neuron dysfunction in two models by pe rforming physiologic and morphometric studies. Background: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of f amilial ALS (FALS), Transgenes with these mutations produce a pattern of lo wer motor neuron degeneration similar to that seen in patients with FALS. I n contrast, mice lacking SOD1 develop subtle motor symptoms by approximatel y 6 months of age. Methods: Physiologic measurements, including motor condu ction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spi nal cords of SOD1-KO and normal mice. Results: In mFALS mice, the motor uni t number in the distal hind limb declined before behavioral abnormalities a ppeared, and motor unit size increased. Compound motor action potential amp litude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal c ords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. Conclusions: The physiologic abnormalitie s in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functio nally impaired in the absence of SOD1.