Wild-type and Mutant SOD1 Share an Aberrant Conformation and a Common Pathogenic Pathway in ALS

Nat Neurosci. 2010 Nov;13(11):1396-403. doi: 10.1038/nn.2660. Epub 2010 Oct 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis* / etiology
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / pathology
  • Antibodies, Anti-Idiotypic
  • Crystallography, X-Ray / methods
  • Epitope Mapping / methods
  • Female
  • Humans
  • Male
  • Mass Spectrometry / methods
  • Middle Aged
  • Models, Molecular
  • Mutation / genetics*
  • Mutation / immunology
  • Oxidation-Reduction
  • Protein Folding
  • Proteostasis Deficiencies / complications*
  • Proteostasis Deficiencies / genetics
  • Proteostasis Deficiencies / pathology
  • Superoxide Dismutase / chemistry
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / immunology
  • Superoxide Dismutase-1

Substances

  • Antibodies, Anti-Idiotypic
  • SOD1 protein, human
  • Superoxide Dismutase
  • Superoxide Dismutase-1