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

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 proteotox...

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Autores principales: Gidalevitz, Tali, Wang, Ning, Deravaj, Tanuja, Alexander-Floyd, Jasmine, Morimoto, Richard I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816611/
https://www.ncbi.nlm.nih.gov/pubmed/24079614
http://dx.doi.org/10.1186/1741-7007-11-100
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author Gidalevitz, Tali
Wang, Ning
Deravaj, Tanuja
Alexander-Floyd, Jasmine
Morimoto, Richard I
author_facet Gidalevitz, Tali
Wang, Ning
Deravaj, Tanuja
Alexander-Floyd, Jasmine
Morimoto, Richard I
author_sort Gidalevitz, Tali
collection PubMed
description 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.
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spelling pubmed-38166112013-11-05 Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease Gidalevitz, Tali Wang, Ning Deravaj, Tanuja Alexander-Floyd, Jasmine Morimoto, Richard I BMC Biol Research Article 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. BioMed Central 2013-09-30 /pmc/articles/PMC3816611/ /pubmed/24079614 http://dx.doi.org/10.1186/1741-7007-11-100 Text en Copyright © 2013 Gidalevitz et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Gidalevitz, Tali
Wang, Ning
Deravaj, Tanuja
Alexander-Floyd, Jasmine
Morimoto, Richard I
Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title_full Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title_fullStr Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title_full_unstemmed Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title_short Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease
title_sort natural genetic variation determines susceptibility to aggregation or toxicity in a c. elegans model for polyglutamine disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816611/
https://www.ncbi.nlm.nih.gov/pubmed/24079614
http://dx.doi.org/10.1186/1741-7007-11-100
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