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.
Highlights
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
We observed an early onset of aggregation in DR1350 background, with on average eight-fold higher number of aggregates in the second larval stage (L2) of Q40DR1350 animals than in Q40Bristol animals (Figure 1b), and a twofold to threefold increase at the late larval stage 4 (L4) (Figure 1c, and data not shown)
We found that the muscle dysfunction index (MDI) overall tracked with enhanced or suppressed aggregation for the five Recombinant inbred lines (RILs) scored (Figures 2b, 3a, 4b)
Summary
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. Genetic variants identified in this way are enormously informative about pathways that affect disease processes and that can, when perturbed, modify disease phenotypes [25,26,27,28,29,30], they are likely to be different from the naturally occurring variations These approaches are designed to identify individual modifier genes with strong phenotypic effects. Because imbalance in proteostasis can indirectly affect the aggregation phenotype of the disease-causing mutation, such genetic intervention may appear as a true modifier
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