Vassall KA, Stubbs HR, Primmer HA, Tong MS, Sullivan SM, Sobering R, Srinivasan S, Briere LA, Dunn SD, Colón W, Meiering EM. Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2210-5. PubMed.
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University of North Carolina, Chapel Hill
In this article, the authors address the contribution of mutant SOD1 stability loss and aggregation to disease severity in ALS. Specifically, they study the propensity of SOD1 mutants to form soluble aggregate species, which have recently been suggested to be primary cytotoxins in ALS. The authors find a weak correlation between the propensity of mutants to form small soluble aggregates and disease severity (duration), which they take as evidence that soluble SOD1 aggregates "[do] not play a dominant role in modulating disease." It is important to note that the evidence presented here does not contradict the hypothesis that soluble SOD1 aggregates are primary contributors to ALS pathogenesis. Rather, the lack of correlation between in vitro aggregation propensity and disease duration underscores the impact of non-genetic factors (e.g., the cellular redox environment) on SOD1 stability and aggregate formation in vivo. In this study, nearly all of the SOD1 mutants studied were in a pseudo-wild-type background in which both free cysteines (at positions 6 and 111) are mutated to serine. Several groups have reported that SOD1's free cysteines stabilize aggregates through the formation of non-native disulfide crosslinking, and our group has found that post-translational modification at Cys-111 destabilizes the native structure. Since free cysteines are apparently involved in SOD1 aggregation, it may not be surprising that the behavior of SOD1 mutants lacking these residues does not correlate with clinical severity of disease.
There is comparatively little quantitative biophysical data on the completely immature SOD1 (disulfide reduced and metal deficient). This paper, which characterizes 12 ALS-associated variants, begins to fill in that gap. The authors then compare their biophysical data to patient survival times. The potential benefits of doing so include developing a better model of proteinopathies in general and ALS in particular, and informing structure-based drug design efforts (i.e., to help researchers avoid targeting innocuous structural defects).
These authors found no correlation between the stability or aggregation of immature SOD1 variants and ALS prognosis.
These results, which on the one hand represent the most comprehensive analysis to date, on the other hand are acknowledged to conflict with studies by other groups implicating disulfide reduced SOD1 in ALS pathogenesis. So what gives? Fortunately, all of these groups are competent biochemists—when they do measure the same variant in the same way, they get comparable results. For better or for worse, however, the same variants and same techniques are not always employed, nor is the same analysis. The devil may be hiding somewhere in these details. With funding levels as low as they've been in recent history, it's not possible for all of these groups to analyze the ~130 ALS-associated SOD1 variants required for a truly comprehensive study. I would like to think that if they could, a consistent picture would result.
University of Massachusetts Medical Center
The paper by Vassall et al. reminds us that finding a common, toxic characteristic (e.g., aggregation propensity) amongst ALS-linked SOD1 mutants is not straightforward. Moreover, the extrapolation of in vitro aggregation kinetics to human disease pathogenesis may fall short because it is difficult to fully recapitulate a complex, in vivo environment within a test tube. The lack of correlation between mutant SOD1 aggregation propensity and ALS disease severity may also reflect that the production of insoluble SOD1 aggregates does not contribute to disease pathogenesis. In fact, much focus has been placed on investigating pre-aggregated forms of neurodegenerative disease associated proteins, such as misfolded soluble species and oligomeric species that are believed to be on-pathway to the large, insoluble aggregates observed in end-stage autopsy patient tissues. Soluble forms (i.e., not higher-order aggregates) of mutant and modified SOD1 proteins have been shown to form aberrant protein interactions, mislocalize within the cell, and inappropriately activate cellular pathways. Perhaps a correlation between one of these parameters and ALS disease severity will be revealed upon further analysis. The results of Vassall et al. underscore the need to consider factors other than in vitro protein aggregation propensities in the context of neurodegeneration. As the authors note, "additional biophysical and biological factors are needed to account for the toxicity of mutant SOD1 in ALS."
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