Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikaryaof mice expressing the SOD1(G93A) mutation of familial amyotrophic lateralsclerosis

Mice expressing the G93A and other mutations of Cu,Zn superoxide dismutase (SOD1(G93A)) are valid models for the familial form of amyotrophic lateral sclerosis (FALS) with SOD1 mutations and, probably, for sporadic ALS. Adult mice become progressively paralyzed and show most of the histopathological lesions reported in sporadic ALS, i.e, neuronal loss, astrogliosis, ubiqui tin and Lewy body-like inclusions, dystrophic axons and fragmentation of th e Golgi apparatus (GA) of motor neurons. In transgenic mice, the mutant pro tein and ubiquitin aggregate within pathological 13 nm thick filaments [Sti eber A, Gonatas JO, Gonatas NK. J Neurol Sci 2,000;173:53-62]. This immunoc ytochemical and quantitative study of mice expressing SOD1(G93A) establishe s the chronological order and cellular localization of aggregates of SOD1 a nd their correlation with fragmentation of the GA. Young asymptomatic mice expressing SOD1(G93A) showed aggregates of mutant SOD1 within neurites, pri or to the detection of SOD1 in the perikarya of spinal cord motor neurons a nd astrocytes. Both dendrites and the periaxonal oligodendroglial cytoplasm , surrounding atrophic axons, contained SOD1 as revealed by immunoelectron microscopy The perikarya of a small percentage of spinal cord motor neurons contained both fragmented GA and aggregates of SOD1; however, about 50% of motor neurons with fragmented GA did not contain SOD1 in the perikaryon, s uggesting that aggregates of mutant protein may not directly cause fragment ation of the GA. The mechanism of the putative toxic effect by the mutant p rotein remains to be clarified. The isolation and biochemical characterizat ion of the filamentous aggregates of mutant protein and ubiquitin from spin al cords of transgenic mice expressing mutations of the SOD1 gene may offer clues on pathogenetic mechanisms. (C) 2000 Elsevier Science B.V. All right s reserved.