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

• Published in: Journal of the neurological sciences Vol. 173; no. 1; pp. 53 - 62
• Main Authors: Stieber, Anna, Gonatas, Jacqueline O, Gonatas, Nicholas K
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01-02-2000; Elsevier Science
• Subjects: 13 nm Filaments; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Golgi apparatus; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Medical sciences; Mice; Mice, Transgenic; Microscopy, Electron; Neurology; Neurons - metabolism; Neurons - ultrastructure; SOD1 G93A; Spinal Cord - metabolism; Spinal Cord - ultrastructure; Superoxide Dismutase - metabolism; Ubiquitin; Ubiquitins - metabolism; Ubiquitin; SOD1 G93A; 13 nm Filaments; SOD1, Cu,Zn superoxide dismutase; GA, Golgi apparatus; SOD1 G93A, the G93A mutation of SOD1; Golgi apparatus; Nervous system diseases; Enzyme; Pathogenesis; Rodentia; Transgenic animal; Amyotrophic lateral sclerosis; Superoxide dismutase; Motor neuron; Zinc; Vertebrata; Mammalia; Mouse; Central nervous system disease; Degenerative disease; Oxidoreductases; Mutation; Copper; Spinal cord disease
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/S0022-510X(99)00300-7

Transgenic mice that express the G93A mutation of human Cu,Zn superoxide dismutase (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 of fragmented neuronal GA in asymptomatic mice, months before the onset of paralysis, suggests that the GA is an early target of the pathological processes causing neuronal degeneration. Transgenic mice expressing human SOD1
G93A have aggregates of mutant protein and ubiquitin in neuronal and glial cytoplasm; they appeared first in the neuropil and later in the perikarya of motor neurons, where they were adjacent to fragmented GA. The aggregates of SOD1
G93A appeared in neuronal perikarya of asymptomatic mice containing fragmented GA. The numbers of neurons with deposits of SOD1
G93A and fragmented GA progressively increased with age. Immuno-electron microscopy using colloidal gold showed labeling of ubiquitin and SOD1 over 13 nm thick cytoplasmic filaments. Spinal cord extracts showed a 20-fold increase of SOD1
G93A in transgenic mice compared to the wild-type protein in controls. The results suggest a causal relationship between the aggregation of mutant SOD1 and ubiquitin, fragmentation of the Golgi apparatus of motor neurons and neurodegeneration.