. Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol. 2008 Jul 29;6(7):e170. PubMed.

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  1. Mutations in SOD1 linked to familial ALS induce the mutant protein to form intracytoplasmic aggregates. A recent study by Wang et al. in PLoS Biology used measures of several biophysical properties of mutant SOD1 to estimate aggregation rates, and then compared the data to clinical data on patient survival for each of the studied mutants. The authors suggest that the rate of mutant protein aggregation could be linked to the relative survival expectancy of individual patients. It is well established for some ALS-linked mutations that a specific point mutation, such as Ala 4 to Val, is associated with a very rapid disease course from onset to death; usually less than two years. The A4V mutation is one of the most common with well over 100 affected individuals having been examined and clinically described. However, the vast majority of SOD1-linked kindreds are much smaller with far fewer clinically evaluated patients. For this reason, one must view the association of a particular property of a given mutant protein to clinical outcomes of patients, with the same mutation, with considerable skepticism.

    Nevertheless, the A4V mutation does appear to significantly destabilize normal structure to induce the aggregation of mutant SOD1. Whether one can definitively argue that clinical data from much smaller families, with slower clinical courses, carry the same weight in demonstrating that slower aggregation rates of mutant SOD1 underlie slower disease courses is less certain. However, if such data are informative, then the study by Wang et al. suggests that the aggregation of mutant protein is linked to the rate of patient decline. Notably, the study does not provide information regarding the pathologic manifestation of mutant SOD1 aggregation in patients, and thus does not provide significant insight as to whether specific types of pathologic features (such as cytoplasmic inclusions) are, or are not, toxic. The data do provide correlative evidence that aggregation of mutant SOD1 could be generating toxic entities that drive one aspect of disease progression. The nature of these toxic entities, however, remains unclear and could take on virtually any physical form such as small oligomeric structure to large filamentous aggregate.

  2. Prof. Borchelt is correct that our study would have benefited from data regarding the pathologic manifestation of aggregates. Unfortunately, most of the primary literature contains only the following information: 1) patient's age at ALS onset, and 2) disease duration. Occasionally the patient’s sex is mentioned. Rarely is critical information such as weight, smoking, activities, drug use, occupation, pathology, SOD1 filter-trap assays, etc., included. While neurologists who publish onset and duration data are to be commended, it is our sincere hope that they (perhaps at patients’ behest) will begin to publish, or at least make available to ALS researchers, more comprehensive epidemiology data. Improved (read “shared”) epidemiology data will almost certainly contribute to our understanding of sporadic ALS.

    Professor Borchelt also writes, “Whether one can definitively argue that clinical data from much smaller families, with slower clinical courses, carry the same weight in demonstrating that slower aggregation rates of mutant SOD1 underlie slower disease courses is less certain.” Again, more epidemiology data may address his concern—we could only consider the >1,000 patients’ data that were available in the literature. Moreover, we did not assume that data from much smaller families carry the same weight as data from larger families. On the contrary, statistical analyses were weighted for the number of patients with a given mutation, thus accounting for (or at least attempting to) family size. For those concerned (as we were) that this weighted statistical analysis could itself result in selection bias, we also performed unweighted statistic analyses. Both sets of analyses were statistically significant.

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