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Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease

From the Ludwig Institute for Cancer Research (Drs. Cleveland, Bruijn, and Ms. Vechio) and the Departments of Medicine and Neuroscience (Dr. Cleveland) and the Division of Cellular and Molecular Medicine (Mr. Marszalek), University of California, La Jolla, CA; the Laboratory of Neuropathology (Drs. Wong, Lee, Borchelt, Sisodia, and Price) and the Departments of Pathology and Neuroscience (Dr. Price), The Johns Hopkins University School of Medicine, Baltimore, MD; and Worcester Foundation for Biomedical Research (Dr. Xu), Shrewsbury, MA.
Address correspondence and reprint requests to Dr. Don W. Cleveland, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093.

Abstract.

To examine the mechanism(s) of disease underlying ALS, transgenic mouse models have been constructed that express aberrant neurofilaments or mutations in the abundant, cytoplasmic enzyme superoxide dismutase 1 (SOD1).In addition to progressive weakness arising from selective motor neuron death, mice expressing a modest level of a point mutant in neurofilament subunit NF-L show most of the pathologic hallmarks observed in familial and sporadic ALS, including perikaryal proximal axonal swellings, axonal degeneration, and severe skeletal muscle atrophy. Additional mice expressing familial ALS-linked mutations in the cytoplasmic enzyme SOD1, the only proven cause of ALS and which accounts for approximate 20% of familial disease, have demonstrated that at least one mutation causes disease through acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity. These animals not only provide a detailed look at the pathogenic progression of disease, but also represent a tool for testing hypotheses concerning the specific mechanism(s) of neuronal death and for testing therapeutic strategies.

NEUROLOGY 1996;47(Suppl 2): S54-S62