Elucidation of the aggregation mechanism of the mutant superoxide dismutase1 (SOD1) in patients with familial amyotrophic lateral sclerosis with SOD1 gene mutation and their animal models

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We have elucidated the aggregation mechanism of the mutant superoxide dismutase1 (SOD1) in patients with familial amyotrophic lateral sclerosis with SOD1 gene mutation and their animal models. This mutant SOD1 aggregation leads to their motor neuron death. Granule-coated fibrils are ultrastructural morphological hallmarks of this mutant SOD1 aggregation toxicity. Maillard reaction [advanced glycation endproduct (AGE) formation] contributes to the granule-coated fibril formation : the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e.,granule-coated fibril formation), which leads to the neuronal cell death. The increase of these granule-coated fibrils means intracellular inclusion formation. When the inclusions have been growing, co-aggregation or sequestration into the inclusions (i.e.,granule-coated fibrils themselves) has been observed for normal cytosolic constitutive proteins, copper chaperone for SOD (chaperone specifically carried copper to SOD1), hepatocyte growth factor (neurotrophic factor), and proxiredoxin/glutathione peroxidase directly regulating a redox system. These are also endogenous mechanisms that accelerate neuronal death.