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From the Department of Neurology (Dr. Shefner), State University of New York Health Science Center at Syracuse, NY; Cephalon, Inc. (Drs. Reaume, Flood, and Scott), West Chester, PA; the Geriatric Research, Education and Clinical Center (Drs. Kowall, Ferrante, and Siwek), Bedford VA Medical Center, MA; and the Cecil B. Day Laboratory for Neuromuscular Research (Dr. Brown and M. Upton–Rice), Massachusetts General Hospital, Boston, MA.
Address correspondence and reprint requests to Dr. J.M. Shefner, Department of Neurology, SUNY Health Science Center, 750 East Adams Street, Syracuse, NY 13210; e-mail: Shefnerj{at}Vax.cs.hscsyr.edu
OBJECTIVE: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies.
BACKGROUND: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age.
METHODS: Physiologic measurements, including motor conduction 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 spinal cords of SOD1-KO and normal mice.
RESULTS: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude 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 cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons.
CONCLUSIONS: The physiologic abnormalities 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 functionally impaired in the absence of SOD1.
Key words: ALS—SOD1—Motor unit estimation.
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