MASSIVE MITOCHONDRIAL DEGENERATION IN MOTOR-NEURONS TRIGGERS THE ONSET OF AMYOTROPHIC-LATERAL-SCLEROSIS IN MICE EXPRESSING A MUTANT SOD1

Authors
Citation
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
Citations number
24
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
02706474
Volume
18
Issue
9
Year of publication
1998
Pages
3241 - 3250
Database
ISI
SICI code
0270-6474(1998)18:9<3241:MMDIMT>2.0.ZU;2-N
Abstract
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.