Human Molecular Genetics Advance Access originally published online on May 30, 2009
Human Molecular Genetics 2009 18(17):3217-3226; doi:10.1093/hmg/ddp260
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Variation in aggregation propensities among ALS-associated variants of SOD1: Correlation to human disease
1 Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA 2 Department of Biochemistry and X-ray Crystallography Core Laboratory, University of Texas Health Science Center and 3 Department of Veterans Affairs, Geriatric Research, Education, and Clinical Center, South Texas Health Care System, San Antonio, TX, USA 4 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
* To whom correspondence should be addressed at: Department of Neuroscience, McKnight Brain Institute, University of Florida, PO Box 100244, Gainesville, FL, USA. Tel: +1 3522940582; Fax: +1 3523928347; Email: merchepa{at}ufl.edu
Received March 23, 2009; Accepted May 28, 2009
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.