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Open Access Research article

Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease

Tali Gidalevitz12*, Ning Wang13, Tanuja Deravaj1, Jasmine Alexander-Floyd2 and Richard I Morimoto1

Author Affiliations

1 Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, USA

2 Department of Biology, Drexel University, Papadakis Integrated Sciences Center Room 418, 3245 Chestnut Street, Philadelphia, PA 19104, USA

3 Current address: Department of Natural Sciences, The University of Virginia’s College at Wise, Wise, VA 24293, USA

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BMC Biology 2013, 11:100  doi:10.1186/1741-7007-11-100

Published: 30 September 2013

Abstract

Background

Monogenic gain-of-function protein aggregation diseases, including Huntington’s disease, exhibit substantial variability in age of onset, penetrance, and clinical symptoms, even between individuals with similar or identical mutations. This difference in phenotypic expression of proteotoxic mutations is proposed to be due, at least in part, to the variability in genetic background. To address this, we examined the role of natural variation in defining the susceptibility of genetically diverse individuals to protein aggregation and toxicity, using the Caenorhabditis elegans polyglutamine model.

Results

Introgression of polyQ40 into three wild genetic backgrounds uncovered wide variation in onset of aggregation and corresponding toxicity, as well as alteration in the cell-specific susceptibility to aggregation. To further dissect these relationships, we established a panel of 21 recombinant inbred lines that showed a broad range of aggregation phenotypes, independent of differences in expression levels. We found that aggregation is a transgressive trait, and does not always correlate with measures of toxicity, such as early onset of muscle dysfunction, egg-laying deficits, or reduced lifespan. Moreover, distinct measures of proteotoxicity were independently modified by the genetic background.

Conclusions

Resistance to protein aggregation and the ability to restrict its associated cellular dysfunction are independently controlled by the natural variation in genetic background, revealing important new considerations in the search for targets for therapeutic intervention in conformational diseases. Thus, our C. elegans model can serve as a powerful tool to dissect the contribution of natural variation to individual susceptibility to proteotoxicity.

Please see related commentary by Kaeberlein, http://www.biomedcentral.com/1741-7007/11/102 webcite.

Keywords:
Protein aggregation; Polyglutamine; Conformational disease; Genetic modifier; Natural variation