Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1

TLDR

Amyotrophic lateral sclerosis involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death; mutations in Cu,Zn superoxide dismutase (SOD1) cause the disease, and transgenic mice with mutant SOD1 recapitulate human ALS pathology. The study aimed to elucidate ALS progression by developing a behavioral assay to monitor disease stages in mutant SOD1 mice. Using this assay, the authors staged disease in G93A mice and correlated stages with pathological features, establishing a sequence leading to motor neuron death. Four disease stages were defined; onset is marked by a sharp decline in muscle strength and a transient surge of mitochondria‑derived vacuoles, with most motor neurons surviving until the terminal stage about nine weeks later, indicating that mutant SOD1 toxicity is mediated by mitochondrial damage that triggers functional decline and clinical onset, and that early‑stage motor neurons could be rescued after diagnosis.

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, ∼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.