Genetic background modifies phenotypic and transcriptional responses in a C. elegans model of α-synuclein toxicity

Yiru A. Wang, Basten L. Snoek, Mark G. Sterken, Joost A.G. Riksen, Jana J. Stastna, Jan E. Kammenga, Simon C. Harvey

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background - Accumulation of protein aggregates are a major hallmark of progressive neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Transgenic Caenorhabditis elegans nematodes expressing the human synaptic protein α-synuclein in body wall muscle show inclusions of aggregated protein, which affects similar genetic pathways as in humans. It is not however known how the effects of α-synuclein expression in C. elegans differs among genetic backgrounds. Here, we compared gene expression patterns and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds.
Results - Transcriptome analysis indicates that α-synuclein expression effects pathways associated with nutrient storage, lipid transportation and ion exchange and that effects vary depending on the genetic background. These gene expression changes predict that a range of phenotypes will be affected by α-synuclein expression. We confirm this, showing that α-synuclein expression delayed development, reduced lifespan, increased rate of matricidal hatching, and slows pharyngeal pumping. Critically, these phenotypic effects depend on the genetic background and coincide with the core changes in gene expression.
Conclusions - Together, our results show genotype-specific effects and core alterations in both gene expression and in phenotype in response to α-synuclein expression. We conclude that the effects of α-synuclein expression are substantially modified by the genetic background, illustrating that genetic background needs to be considered in C. elegans models of neurodegenerative disease
Original languageEnglish
Article number232
Number of pages12
JournalBMC Genomics
Volume20
Issue number1
DOIs
Publication statusPublished - 20 Mar 2019

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Synucleins
Caenorhabditis elegans
Gene Expression
Neurodegenerative Diseases
Phenotype
Genetic Background
Ion Exchange
Gene Expression Profiling
Parkinson Disease
Alzheimer Disease
Proteins
Genotype
Lipids
Food
Muscles

Cite this

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title = "Genetic background modifies phenotypic and transcriptional responses in a C. elegans model of α-synuclein toxicity",
abstract = "Background - Accumulation of protein aggregates are a major hallmark of progressive neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Transgenic Caenorhabditis elegans nematodes expressing the human synaptic protein α-synuclein in body wall muscle show inclusions of aggregated protein, which affects similar genetic pathways as in humans. It is not however known how the effects of α-synuclein expression in C. elegans differs among genetic backgrounds. Here, we compared gene expression patterns and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds.Results - Transcriptome analysis indicates that α-synuclein expression effects pathways associated with nutrient storage, lipid transportation and ion exchange and that effects vary depending on the genetic background. These gene expression changes predict that a range of phenotypes will be affected by α-synuclein expression. We confirm this, showing that α-synuclein expression delayed development, reduced lifespan, increased rate of matricidal hatching, and slows pharyngeal pumping. Critically, these phenotypic effects depend on the genetic background and coincide with the core changes in gene expression.Conclusions - Together, our results show genotype-specific effects and core alterations in both gene expression and in phenotype in response to α-synuclein expression. We conclude that the effects of α-synuclein expression are substantially modified by the genetic background, illustrating that genetic background needs to be considered in C. elegans models of neurodegenerative disease",
author = "Wang, {Yiru A.} and Snoek, {Basten L.} and Sterken, {Mark G.} and Riksen, {Joost A.G.} and Stastna, {Jana J.} and Kammenga, {Jan E.} and Harvey, {Simon C.}",
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Genetic background modifies phenotypic and transcriptional responses in a C. elegans model of α-synuclein toxicity. / Wang, Yiru A.; Snoek, Basten L.; Sterken, Mark G.; Riksen, Joost A.G.; Stastna, Jana J.; Kammenga, Jan E.; Harvey, Simon C.

In: BMC Genomics, Vol. 20, No. 1, 232, 20.03.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genetic background modifies phenotypic and transcriptional responses in a C. elegans model of α-synuclein toxicity

AU - Wang, Yiru A.

AU - Snoek, Basten L.

AU - Sterken, Mark G.

AU - Riksen, Joost A.G.

AU - Stastna, Jana J.

AU - Kammenga, Jan E.

AU - Harvey, Simon C.

PY - 2019/3/20

Y1 - 2019/3/20

N2 - Background - Accumulation of protein aggregates are a major hallmark of progressive neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Transgenic Caenorhabditis elegans nematodes expressing the human synaptic protein α-synuclein in body wall muscle show inclusions of aggregated protein, which affects similar genetic pathways as in humans. It is not however known how the effects of α-synuclein expression in C. elegans differs among genetic backgrounds. Here, we compared gene expression patterns and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds.Results - Transcriptome analysis indicates that α-synuclein expression effects pathways associated with nutrient storage, lipid transportation and ion exchange and that effects vary depending on the genetic background. These gene expression changes predict that a range of phenotypes will be affected by α-synuclein expression. We confirm this, showing that α-synuclein expression delayed development, reduced lifespan, increased rate of matricidal hatching, and slows pharyngeal pumping. Critically, these phenotypic effects depend on the genetic background and coincide with the core changes in gene expression.Conclusions - Together, our results show genotype-specific effects and core alterations in both gene expression and in phenotype in response to α-synuclein expression. We conclude that the effects of α-synuclein expression are substantially modified by the genetic background, illustrating that genetic background needs to be considered in C. elegans models of neurodegenerative disease

AB - Background - Accumulation of protein aggregates are a major hallmark of progressive neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Transgenic Caenorhabditis elegans nematodes expressing the human synaptic protein α-synuclein in body wall muscle show inclusions of aggregated protein, which affects similar genetic pathways as in humans. It is not however known how the effects of α-synuclein expression in C. elegans differs among genetic backgrounds. Here, we compared gene expression patterns and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds.Results - Transcriptome analysis indicates that α-synuclein expression effects pathways associated with nutrient storage, lipid transportation and ion exchange and that effects vary depending on the genetic background. These gene expression changes predict that a range of phenotypes will be affected by α-synuclein expression. We confirm this, showing that α-synuclein expression delayed development, reduced lifespan, increased rate of matricidal hatching, and slows pharyngeal pumping. Critically, these phenotypic effects depend on the genetic background and coincide with the core changes in gene expression.Conclusions - Together, our results show genotype-specific effects and core alterations in both gene expression and in phenotype in response to α-synuclein expression. We conclude that the effects of α-synuclein expression are substantially modified by the genetic background, illustrating that genetic background needs to be considered in C. elegans models of neurodegenerative disease

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