Nature neuroscience, 2010-11, Vol.13 (11), p.1396-1403
2010
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- Autor(en) / Beteiligte
- Titel
- Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS
- Ist Teil von
- Nature neuroscience, 2010-11, Vol.13 (11), p.1396-1403
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Could similar changes in SOD1 underlie both familial and sporadic ALS? Here, Bosco et al . find that wild-type SOD1 from sporadic ALS tissues shows conformational changes similar to those seen in familial ALS and that aberrant wild-type SOD1 can be pathogenic, potentially as a result of the same SOD1-dependent mechanism seen in familial 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-6256eISSN: 1546-1726DOI: 10.1038/nn.2660Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2967729
- Format
- –
- Schlagworte
- 631/378/1689/1285, 631/378/1689/364, 631/378/1697, 631/80/86, Adult, Aged, Amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis - etiology, Amyotrophic Lateral Sclerosis - genetics, Amyotrophic Lateral Sclerosis - pathology, Animal Genetics and Genomics, Antibodies, Anti-Idiotypic, Behavioral Sciences, Biological Techniques, Biomedical and Life Sciences, Biomedicine, Care and treatment, Crystallography, X-Ray - methods, Diagnosis, Epitope Mapping - methods, Female, Gene mutations, Genetic aspects, Health aspects, Humans, Hypotheses, Kinases, Male, Mass Spectrometry - methods, Middle Aged, Models, Molecular, Monoclonal antibodies, Motor neurons, Mutation, Mutation - genetics, Mutation - immunology, Neurobiology, Neurons, Neurosciences, Oxidation, Oxidation-Reduction, Pathogenesis, Physiological aspects, Protein Folding, Proteins, Proteostasis Deficiencies - complications, Proteostasis Deficiencies - genetics, Proteostasis Deficiencies - pathology, Superoxide Dismutase - chemistry, Superoxide Dismutase - genetics, Superoxide Dismutase - immunology, Superoxide Dismutase-1