TIME-COURSE OF NEUROPATHOLOGY IN THE SPINAL-CORD OF G86R SUPEROXIDE-DISMUTASE TRANSGENIC MICE

Transgenic mice with a G86R mutation in the mouse superoxide dismutase (SOD-1) gene, which corresponds to a mutation observed in familial am yotrophic lateral sclerosis (ALS), display progressive motor dysfuncti on leading to paralysis and premature death. In endstage SOD-1 transge nic mice, there is marked loss of spinal motor neurons and interneuron s, accumulation of phosphorylated neurofilament inclusions, and reacti ve astrocytosis. The present study details the time course and ultrast ructural appearance of these pathologic changes and correlates the tim ing of these events with the behavioral symptoms. There is no signific ant reduction in the number of total neurons, motor neurons, or intern eurons in the ventral spinal cord of presymptomatic mice, as compared to age-matched control mice. In contrast, there is a significant reduc tion in the number of total neurons (-23.5%), motor neurons (-28.9%), and interneurons (-23.5%) in symptomatic SOD-1 transgenic mice. This n euron loss correlates temporally with the onset of reactive astrocytos is and the appearance of phosphorylated neurofilament inclusions. The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degeneration in the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal cord. In addition, the late onset and rapid progression of neuron loss suggest that a toxic property is accumulating while the SOD-1 transge nic mice are presymptomatic, and that this toxic property must reach a threshold level before the onset of neuronal degeneration. (C) 1998 W iley-Liss, Inc.