Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegansmodel for polyglutamine diseaseReport as inadecuate




Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegansmodel for polyglutamine disease - Download this document for free, or read online. Document in PDF available to download.

BMC Biology

, 11:100

First Online: 30 September 2013Received: 25 June 2013Accepted: 11 September 2013DOI: 10.1186-1741-7007-11-100

Cite this article as: Gidalevitz, T., Wang, N., Deravaj, T. et al. BMC Biol 2013 11: 100. doi:10.1186-1741-7007-11-100

Abstract

BackgroundMonogenic 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.

ResultsIntrogression 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.

ConclusionsResistance 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.

KeywordsProtein aggregation Polyglutamine Conformational disease Genetic modifier Natural variation Electronic supplementary materialThe online version of this article doi:10.1186-1741-7007-11-100 contains supplementary material, which is available to authorized users.

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Author: Tali Gidalevitz - Ning Wang - Tanuja Deravaj - Jasmine Alexander-Floyd - Richard I Morimoto

Source: https://link.springer.com/







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