Variation in aggregation propensities among ALS-associated variants of SOD1: Correlation to human disease

Mercedes Prudencio, P. John Hart, David R. Borchelt, Peter M. Andersen

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


To date, 146 different mutations in superoxide dismutase 1 (SOD1) have been identified in patients with familial amyotrophic lateral sclerosis (ALS). The mean age of disease onset in patients inheriting mutations in SOD1 is 45-47 years of age. However, although the length of disease duration is highly variable, there are examples of consistent disease durations associated with specific mutations (e. g. A4V, less than 2 years). In the present study, we have used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different variants of mutant SOD1. Using a reliable cell culture assay, we show that all ALS-associated mutations in SOD1 increase the inherent aggregation propensity of the protein. However, the relative propensity to do so varied considerably among mutants. We were not able to explain the variation in aggregation rates by differences in known protein properties such as enzyme activity, protein thermostability, mutation position or degree of change in protein charge. Similarly, we were not able to explain variability in the duration of disease in SOD1-associated ALS pedigrees by these properties. However, we find that the majority of pedigrees in which patients exhibit reproducibly short disease durations are associated with mutations that show a high inherent propensity to induce aggregation of SOD1.

Original languageEnglish (US)
Pages (from-to)3217-3226
Number of pages10
JournalHuman molecular genetics
Issue number17
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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