Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.

Publication Type:

Journal Article

Authors:

Bosco, Daryl A; Morfini, Gerardo; Karabacak, N Murat; Song, Yuyu; Gros-Louis, François; Pasinelli, Piera; Goolsby, Holly; Fontaine, Benjamin A; Lemay, Nathan; McKenna-Yasek, Diane; Frosch, Matthew P; Agar, Jeffrey N; J-P Julien; Brady, Scott T; Brown, Robert H

Source:

Nat Neurosci, Volume 13, Issue 11, p.1396-403 (2010)

Keywords:

Adult, Aged, Amyotrophic Lateral Sclerosis, Antibodies, Anti-Idiotypic, Crystallography, X-Ray, Epitope Mapping, Female, Humans, Male, Mass Spectrometry, Middle Aged, Models, Molecular, Mutation, Oxidation-Reduction, Protein Folding, Proteostasis Deficiencies, Superoxide Dismutase

Abstract:

<p>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.</p>