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Previous Article | Next Article
The Journal of Neuroscience, May 1, 1998, 18(9):3241-3250
Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1
Jiming Kong1 and Zuoshang Xu2 Departments of 1 Pharmacology and Molecular Toxicology and 2 Cell Biology, University of Massachusetts Medical School, Worcester Foundation Campus, Shrewsbury, Massachusetts 01545
Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase (SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop symptoms and pathology similar to those in human ALS. To understand the disease mechanism, we developed a simple behavioral assay for disease progression in mice. Using this assay, we defined four stages of the disease in mice expressing G93A mutant SOD1. By studying mice with defined disease stages, we tied several pathological features into a coherent sequence of events leading to motor neuron death. We show that onset of the disease involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neuron death. Most motor neurons do not die until the terminal stage, ~9 weeks after disease onset. These results indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this damage triggers the functional decline of motor neurons and the clinical onset of ALS. The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis.
Key words: ALS; mitochondria; SOD1; paralysis; motor neuron; degeneration; spinal cord
Copyright © 1998 Society for Neuroscience 0270-6474/98/1893241-10$05.00/0
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