From Charcot to SOD1: Review Mechanisms of Selective Motor Neuron Death in ALS sets of mice expressing different SOD1 mutants, which in each case provoke disease with elevated (Wong et al., 1995) or unchanged (Ripps et al., 1995; Bruijn et al., 1997b) SOD1 activity, while SOD1 null mice live to adulthood and do not develop motor neuron disease

Don W. Cleveland* Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience University of California, San Diego La Jolla, California 92093 (Reaume et al., 1996). Further, some mutants such as SOD1G37R retain full specific activity (Borchelt et al., The sixth anniversary has just passed since the land- 1994), while neither the age of onset nor rapidity of mark discovery (Rosen et al., 1993) that mutation in the progression of human disease correlate with dismutase enzyme superoxide dismutase 1 (SOD1) is a primary activity levels (Cudkowicz et al., 1997). The inescapable cause of a proportion of a dominantly inherited form conclusion from this abundance of evidence is that the of amyotrophic lateral sclerosis (ALS), more familiarly mutants have acquired one or more toxic properties, known in the United States as Lou Gehrig’s disease. irrespective of the amount of SOD1 activity each retains. First described by Charcot 124 years before that, the