Aggregation of ubiquitin and a mutant ALS-linked SOD1 protein correlate with disease progression and fragmentation of the Golgi apparatus

Transgenic mice that express the G93A mutation of human Cu,Zn superoxide di smutase (SOD1(G93A)), found in familial amyotrophic lateral sclerosis (FALS ), showed clinical symptoms and histopathological changes of sporadic ALS, including fragmentation of the neuronal Golgi apparatus (GA). The finding o f fragmented neuronal GA in asymptomatic mice, months before the onset of p aralysis, suggests that the GA is an early target of the pathological proce sses causing neuronal degeneration. Transgenic mice expressing human SOD1(G 93A) have aggregates of mutant protein and ubiquitin in neuronal and glial cytoplasm; they appeared first in the neuropil and later in the perikarya o f motor neurons, where they were adjacent to fragmented GA. The aggregates of SOD1(G93A) appeared in neuronal perikarya of asymptomatic mice containin g fragmented GA. The numbers of neurons with deposits of SOD1(G93A) and fra gmented GA progressively increased with age. Immune-electron microscopy usi ng colloidal gold showed labeling of ubiquitin and SOD1 over 13 nm thick cy toplasmic filaments. Spinal cord extracts showed a 20-fold increase of SOD1 (G93A) in transgenic mice compared to the wild-type protein in controls. Th e results suggest a causal relationship between the aggregation of mutant S OD1 and ubiquitin, fragmentation of the Golgi apparatus of motor neurons an d neurodegeneration. (C) 2000 Elsevier Science B.V. All rights reserved.