Pratt AJ, Shin DS, Merz GE, Rambo RP, Lancaster WA, Dyer KN, Borbat PP, Poole FL 2nd, Adams MW, Freed JH, Crane BR, Tainer JA, Getzoff ED. Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):E4568-76. Epub 2014 Oct 14 PubMed.
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University of Florence
The work by Pratt et al. is important because it strengthens the hypothesis that decreased stability of SOD1 mutants leads to cytotoxicity in ALS patients. However, a critical question remains unanswered in SOD1-linked ALS. Are aggregates of SOD1 mutants the cause of the toxicity, and do their formation kinetics impact the severity of disease, or are aggregates and toxicity unrelated consequences of a common root cause? Indeed, unfolded or misfolded SOD1 species, which have been observed in cell culture models, could play a role in the onset of the disease. Hopefully, further progress will be made when structural characterization—of either aggregated or misfolded SOD1—is carried out in the physiological environment of the cell.
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