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

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.

The overdue promise of short tandem repeat variation for heritability

“…For instance, experiments in Caenorhabditis elegans and human cells indicate that the phenotypic effects of proteins with expanded polyQ tracts are modulated by genetic background [67], or by variants in interacting proteins [68]. In humans, genetic association studies indicate the existence of genetic modifiers of polyQ expansion disorders for both Huntington’s disease [69] and spinocerebellar ataxias [70].…”

Therapeutic Targeting of Misfolding and Conformational Change in α 1 -Antitrypsin Deficiency

“…It has been used to study misfolding protein systems, including neuroserpin [94], polyglutamine repeat proteins [95], amyloid-β [96] and α 1 -antitrypsin [97]. Basic cellular physiological processes (e.g., protein synthesis, secretion and degradation) are relatively well conserved between C. elegans and humans, and it can be easily manipulated by transgenic approaches and RNA interference (RNAi) screening [98].…”

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“…This may explain the higher propensity to aggregation of the mutant disease-related proteins, in order to uncovering onset and phenotypes of disease patterns [27]. Regardless of the toxicity and aggregation of misfolded proteins, other factors leading to the variable complex traits could possibly include multiple additive or allele interactions, with the consequence of underlying intervention strategies at onset and/or in progression of disease.…”