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

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.
Keywords: Natural variation, Gene expression profile, Protein aggregation, α-Synuclein, Genetic background, Caenorhabditis
elegans