Abstract
Our objective was to test the hypothesis that aberrantly modified forms of superoxide dismutase (SOD1) influence the disease course for sporadic amyotrophic lateral sclerosis (SALS). We probed for anti-SOD1 antibodies (IgM and IgG) against both the normal and aberrantly oxidized-SOD1 (SODox) antigens in sera from patients with SALS, subjects diagnosed with other neurological disorders and healthy individuals, and correlated the levels of these antibodies to disease duration and/or severity. Anti-SOD1 antibodies were detected in all cohorts; however, a subset of ∼5–10% of SALS cases exhibited elevated levels of anti-SOD1 antibodies. Those SALS cases with relatively high levels of IgM antibodies against SODox exhibit a longer survival of 6.4 years, compared to subjects lacking these antibodies. By contrast, SALS subjects expressing higher levels of IgG antibodies reactive for the normal WT-SOD1 antigen exhibit a shorter survival of 4.1 years. Anti-SOD1 antibody levels did not correlate with disease severity in either the Alzheimer's or Parkinson's disease cohorts. In conclusion, the association of longer survival with elevated levels of anti-SODox antibodies suggests that these antibodies may be protective. By extension, these data implicate aberrantly modified forms of WT-SOD1 (e.g. oxidized SOD1) in SALS pathogenesis. In contrast, an immune response against the normal WT-SOD1 appears to be disadvantageous in SALS, possibly because the anti-oxidizing activity of normal WT-SOD1 is beneficial to SALS individuals.
Acknowledgements
We thank Anne Hunt and the Eunice Kennedy Shriver Center at the University of Massachusetts Medical School (UMMS) for statistical analyses, the UMMS Proteomic and Mass spectrometry Core facility at UMMS, the Northeast ALS Consortium and the Neurology Clinical Trial Unit for contributing sera samples. We acknowledge financial support from the ALS Therapy Alliance-CVS Pharmacy (D.A.B.), the ALS Association (D.A.B., and R.H.B. Jr), the US National Institutes of Health (D.A.B. (National Institute on Neurological Disorders and Stroke)), R.H.B. Jr (National Institute on Neurological Disorders and Stroke), the Angel Fund (R.H.B. Jr) and Project ALS (R.H.B. Jr).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.