UMMS Affiliation

Department of Pharmacology and Molecular Toxicology; Department of Cell Biology

Date

5-9-1998

Document Type

Article

Subjects

Amyotrophic Lateral Sclerosis; Animals; Axons; Disease Progression; Gene Expression Regulation, Enzymologic; Humans; Mice; Mice, Transgenic; Mitochondrial Encephalomyopathies; Motor Neurons; Mutation; Nerve Degeneration; Spinal Cord; Superoxide Dismutase

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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, approximately 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.

Rights and Permissions

Citation: J Neurosci. 1998 May 1;18(9):3241-50.

Related Resources

Link to Article in PubMed

Journal Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

PubMed ID

9547233

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