. Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5505-10. PubMed.


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  1. This recent paper by Glass and coworkers reports further insight into the recognition of misfolded SOD1 by the conformation-dependent antibody C4F6. This antibody was originally isolated by Jean-Pierre Julien in 2007. This antibody was prepared by immunization of mice with recombinant human SOD1 containing the G93A mutation associated with familial ALS. It had weak immunoreactivity with wild-type SOD1, but it reacted with other mutant forms of SOD1 such as the G37R mutation, indicating that it recognizes a conformation-dependent epitope that does not depend on the specific amino acid substitution. Subsequent work showed that oxidation of wild-type SOD1 causes it to react with C4F6. Here the authors report that "C4F6 reacted only with mutant SOD1 and showed remarkable selectivity for disease-affected tissues and cells." Unaffected cells in adjacent regions were not immunoreactive, even though they expressed high levels of mutant SOD1. These results indicate that C4F6 is exquisitely selective for at least a subset of the SOD1 pathology in ALS.

    Conformation-dependent antibodies are increasingly recognized as pathology-specific reagents that give researchers a clearer and more selective view of the pathological species of misfolded proteins and distinguish them from the natively folded protein. This is especially important in view of recent findings that the same protein can adopt several different conformations, analogous to prion stains, raising the question of whether the different strains may have different significance for pathogenesis. Conformation-dependent monoclonal antibodies can recognize and distinguish this structural variation. The immune system seems to be exquisitely sensitive to alterations in protein structure because of the strong immunological tolerance for natively folded proteins. The majority of antibodies produced against a pathologically misfolded protein immunogen appear to be conformation dependent, and this type of antibody has been raised against most of the proteins that are associated with protein misfolding diseases. How the epitopes that these antibodies recognize behave in experiments can be quite different. For example, routine sample preparation methods that denature proteins, such as SDS use and paraffin embedding or antigen retrieval, can either create or destroy immunoreactivity. The authors here show that SDS treatment of G93A SOD1 from unaffected tissue causes it to be recognized by C4F6, indicating that SDS induces the misfolding of mutant SOD1 to form the immunoreactive epitope. The opposite result can also be obtained, and protein denaturation can destroy the epitope and prevent immunodetection. This means that it is unwise to presume that normal laboratory procedures that denature proteins will be adequate to observe pathology-specific conformational epitopes. A good place to start is with tissue and protein in a native state and then optimize the methods for the specific detection of the pathologically misfolded species. Conformation-dependent antibodies have a lot to tell us about the mechanisms of pathogenesis in protein misfolding diseases if we only listen.

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