NEUROPATHOLOGICAL CHANGES IN 2 LINES OF MICE CARRYING A TRANSGENE FORMUTANT HUMAN CU,ZN SOD, AND IN MICE OVEREXPRESSING WILD-TYPE HUMAN SOD - A MODEL OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS (FALS)

Two different lines of mice, G1 and G20, carrying a transgene for a mu tant form of Cu,Zn SOD, found in a family with familial amyotrophic la teral sclerosis (FALS), develop clinical and pathological changes whic h are, in their late stages, strikingly similar to those in human dise ase. We have analyzed the distribution and characteristics of lesions in the central and peripheral nervous systems of such mice. The most a ffected structure was the spinal cord, followed by the medulla, pens a nd midbrain. The early stages of the disease were characterized by vac uolar degeneration of anterior horn neurons and their processes, while , in the late stages, the main changes consisted of neuronal loss and atrophy of the anterior horns and the deposition in these areas of mul tiple filamentous inclusions resembling Lewy bodies. In the late stage s of the disease, the white matter of the spinal cord was also involve d, particularly in the anterior and lateral columns. Posterior columns were also involved, but to a much lesser degree. The brainstem struct ures also showed vacuolar degeneration of several motor nuclei and of several groups neurons in the reticular formation. Anterior roots and peripheral nerves showed the classical features of Wallerian degenerat ion. The dorsal root ganglia, with rare exceptions, were unremarkable. The posterior roots showed mild changes in the most severely affected mice. Changes in these two affected lines were compared to changes in mice overexpressing wild type, rather than mutant human Cu,Zn SOD. Th ese mice never developed clinical disease, although, pathologically, t hey developed very mild vacuolar changes in the anterior horns of the spinal cord and in motor axons, This study shows that although simple overexpression of SOD may be injurious to motor neurons, albeit very m ildly, the mutant form is necessary to produce both clinical disease a nd severe pathological changes which, in the chronic stage of the dise ase, have striking similarities to human familial ALS. A dominant gain of function, therefore, is the most likely pathogenesis of tissue inj ury induced by mutations in Cu,Zn SOD.