Early vacuolization and mitochondrial damage in motor neurons of FALS miceare not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity

Overexpression of mutated superoxide dismutase (SOD1) in transgenic mice ca uses a progressive motor neuron degeneration in the spinal cord similar to that in human amyotrophic lateral sclerosis (ALS). Ultrastructural analysis of motor neurons at different stages of the disease in transgenic C57BL/6 mice carrying the G93A mutation of SOD1 showed, at about 2 weeks of age, mu ch earlier than the initial symptoms of the disease, microvacuoles in the c ytoplasm, with marked swelling of the mitochondria. Nuclei with an apoptoti c morphology were never observed in these motor neurons. Swollen mitochondr ia were also seen in the distal part of motor axons of phrenic nerves and i n the large axons of sciatic nerves before the onset of the disease, but no mitochondrial alterations were seen in skeletal muscles or in the small sc iatic nerve axons. Moreover, we found no apparent changes in the histochemi cal reactivity of cytochrome oxidase in motor neurons of transgenic mice ev en at the advanced sta-e of the disease, suggesting that partial neuronal a ctivity in these cells may be maintained despite the altered mitochondria. Immunoreactivity for human SOD1 was high around vacuoles in the motor neuro ns of transgenic mice but no cytoplasmic intracellular SOD1 aggregates were observed. Our data indicate that mitochondrial swelling may be an importan t factor triggering the cascade leading to progressive motor neuron death. Activation of the mitochondrial permeability transition pore may be involve d in this process, through excitotoxicity or other neurotoxic stimuli. (C) 2001 Elsevier Science B.V. All rights reserved.