Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS
Copyright policy )Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.
- University of Illinois at Chicago United States
- Harvard University United States
- Brandeis University United States
- UMass Memorial Medical Center United States
- MASSACHUSETTS GENERAL HOSPITAL
Adult, Male, Models, Molecular, Protein Folding, Crystallography, X-Ray, Antibodies, Article, Mass Spectrometry, Superoxide Dismutase-1, Models, Medicine and Health Sciences, Humans, Proteostasis Deficiencies, Aged, Crystallography, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Molecular, Middle Aged, 540, Antibodies, Anti-Idiotypic, Anti-Idiotypic, Mutation, X-Ray, Female, Oxidation-Reduction, Epitope Mapping
Adult, Male, Models, Molecular, Protein Folding, Crystallography, X-Ray, Antibodies, Article, Mass Spectrometry, Superoxide Dismutase-1, Models, Medicine and Health Sciences, Humans, Proteostasis Deficiencies, Aged, Crystallography, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Molecular, Middle Aged, 540, Antibodies, Anti-Idiotypic, Anti-Idiotypic, Mutation, X-Ray, Female, Oxidation-Reduction, Epitope Mapping
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