Jm. Kong et Zs. Xu, MASSIVE MITOCHONDRIAL DEGENERATION IN MOTOR-NEURONS TRIGGERS THE ONSET OF AMYOTROPHIC-LATERAL-SCLEROSIS IN MICE EXPRESSING A MUTANT SOD1, The Journal of neuroscience, 18(9), 1998, pp. 3241-3250
Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration
, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn su
peroxide dismutase (SOD1) are one cause of the disease. Mice transgeni
c 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 SOD
1. By studying mice with defined disease stages, we tied several patho
logical features into a coherent sequence of events leading to motor n
euron death. We show that onset of the disease involves a sharp declin
e of muscle strength and a transient explosive increase in vacuoles de
rived from degenerating mitochondria, but little motor neuron death. M
ost motor neurons do not die until the terminal stage, similar to 9 we
eks after disease onset. These results indicate that mutant SOD1 toxic
ity is mediated by damage to mitochondria in motor neurons, and this d
amage triggers the functional decline of motor neurons and the clinica
l onset of ALS. The absence of massive motor neuron death at the early
stages of the disease indicates that the majority of motor neurons co
uld be rescued after clinical diagnosis.