Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 68, Issue 4, Pages 365-373Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e31819ba185
Keywords
Aggregates; Amyotrophic lateral sclerosis; Astrocytes; H46R; Mitochondria; SOD1; Transgenic mice
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Funding
- Ministry of Education, Culture, Sports, Science and Technology [(18500280)]
- Japan Amyotrophic Lateral Sclerosis Association
- Ministry of Health, Labor and Welfare in Japan
- Grants-in-Aid for Scientific Research [18500280] Funding Source: KAKEN
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We examined morphological alterations in the mitochondria in the spinal cord of H46R mutant Cu/Zn Superoxide dismutase transgenic mice: these mice serve as a model for human familial amyotrophic lateral sclerosis. The disease in the mice is characterized by initial muscle weakness and atrophy in the legs, very long clinical courses, and widespread pathological changes of the spinal cord that extend beyond the motor system and includes many neuropil agregates that lack vacuoles. At the preclinical stage, we found alterations in the mitochondrial cristae that included focal electron-dense changes, whorled membranous and electron-dense amorphous structures, and out-ward projections of outer and inner membranes predominantly in proximal axons. At the overt disease stage, these mitochondrial alterations were more frequent and were also found in somata. dendrites, presynaptic terminals, and astrocyte cytoplasm. By immunoelectron microscopy, no accumulations of Cu/Zn superoxide dismutase- or ubiquitin-positive immunogold particles were observed in either normal-appearing or abnormal mitochondria. These findings suggest that predominant mitochondrial alterations in the proximal axons begin in the preclinical stage and may be involved in the pathogenetic mechanisms of motor neuron degeneration in these transgenic mice via disruption of the axonal transport of substrates necessary for neuronal viability: this disruption may lead to motor neuron death.
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