Nonamyloid aggregates arising from mature copper/zinc superoxide dismutases resemble those observed in amyotrophic lateral sclerosis

J Biol Chem. 2010 Dec 31;285(53):41701-11. doi: 10.1074/jbc.M110.113696. Epub 2010 Oct 25.


Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self- or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Disulfides / chemistry
  • Enzyme-Linked Immunosorbent Assay / methods
  • Metals / chemistry
  • Mice
  • Microscopy, Atomic Force / methods
  • Molecular Conformation
  • Mutation
  • Nervous System Diseases / metabolism
  • Protein Conformation
  • Protein Interaction Mapping
  • Superoxide Dismutase / chemistry*
  • Superoxide Dismutase / genetics


  • Amyloid
  • Disulfides
  • Metals
  • Superoxide Dismutase