title: Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity.
abstract: Overexpression of mutated superoxide dismutase (SOD1) in transgenic mice causes 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, much earlier than the initial symptoms of the disease, microvacuoles in the cytoplasm, with marked swelling of the mitochondria. Nuclei with an apoptotic morphology were never observed in these motor neurons. Swollen mitochondria were also seen in the distal part of motor axons of phrenic nerves and in 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 sciatic nerve axons. Moreover, we found no apparent changes in the histochemical reactivity of cytochrome oxidase in motor neurons of transgenic mice even at the advanced stage of the disease, suggesting that partial neuronal activity in these cells may be maintained despite the altered mitochondria. Immunoreactivity for human SOD1 was high around vacuoles in the motor neurons of transgenic mice but no cytoplasmic intracellular SOD1 aggregates were observed. Our data indicate that mitochondrial swelling may be an important factor triggering the cascade leading to progressive motor neuron death. Activation of the mitochondrial permeability transition pore may be involved in this process, through excitotoxicity or other neurotoxic stimuli.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157, Milan, Italy. Bendotti@marionegri.it
authors.forename: C
authors.initials: C
authors.lastname: Bendotti
authors.forename: N
authors.initials: N
authors.lastname: Calvaresi
authors.forename: L
authors.initials: L
authors.lastname: Chiveri
authors.forename: A
authors.initials: A
authors.lastname: Prelle
authors.forename: M
authors.initials: M
authors.lastname: Moggio
authors.forename: M
authors.initials: M
authors.lastname: Braga
authors.forename: V
authors.initials: V
authors.lastname: Silani
authors.forename: S
authors.initials: S
authors.lastname: De Biasi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008161:Lumbosacral Region; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology*; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D018482:Muscle, Skeletal / Q000648:ultrastructure; D010791:Phrenic Nerve / Q000473:pathology / Q000648:ultrastructure; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014617:Vacuoles / Q000473:pathology* / Q000648:ultrastructure
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV