Biomolecular Research Group, School of Human and Life Sciences, Canterbury Christ Church University, North Holmes Road, Canterbury, CT1 1QU, UK.
Laboratory of Nematology, Wageningen University, 6708, PB, Wageningen, The Netherlands.
BMC Genomics. 2019 Mar 20;20(1):232. doi: 10.1186/s12864-019-5597-1.
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.
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.
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.
蛋白质聚集体的积累是帕金森病和阿尔茨海默病等进行性神经退行性疾病的主要标志。在体壁肌肉中表达人类突触蛋白 α-突触核蛋白的转基因秀丽隐杆线虫表现出聚集蛋白的包涵体，这影响了与人类相似的遗传途径。然而，目前尚不清楚α-突触核蛋白在秀丽隐杆线虫中的表达如何在遗传背景之间存在差异。在这里，我们比较了基因表达模式，并研究了转基因α-突触核蛋白在五种不同秀丽隐杆线虫遗传背景中的表型后果。
转录组分析表明，α-突触核蛋白的表达影响与营养储存、脂质运输和离子交换相关的途径，并且影响取决于遗传背景。这些基因表达变化表明，一系列表型将受到α-突触核蛋白表达的影响。我们证实了这一点，表明α-突触核蛋白的表达会延迟发育、降低寿命、增加杀母孵化率并减缓咽泵的速度。至关重要的是，这些表型效应取决于遗传背景，并与基因表达的核心变化相吻合。
总之，我们的结果表明，α-突触核蛋白表达会引起特定基因型的效应以及基因表达和表型的核心改变。我们得出结论，α-突触核蛋白表达的影响受到遗传背景的极大影响，这说明了在神经退行性疾病的秀丽隐杆线虫模型中需要考虑遗传背景。
