Huang Yuqing, Wang Yiru A, van Sluijs Lisa, Vogels Demi H J, Chen Yuzhi, Tegelbeckers Vivian I P, Schoonderwoerd Steven, Riksen Joost A G, Kammenga Jan E, Harvey Simon C, Sterken Mark G
Laboratory of Nematology, Wageningen University & Research, Droevendaalsesteeg 1, 6708PB, Wageningen, the Netherlands.
Faculty of Engineering and Science, University of Greenwich, Medway ME4 4TB, United Kingdom.
Hum Mol Genet. 2024 Dec 6;33(24):2123-2132. doi: 10.1093/hmg/ddae148.
Protein aggregation of α-synuclein (αS) is a genetic and neuropathological hallmark of Parkinson's disease (PD). Studies in the model nematode Caenorhabditis elegans suggested that variation of αS aggregation depends on the genetic background. However, which genes and genetic modifiers underlie individual differences in αS pathology remains unknown. To study the genotypic-phenotypic relationship of αS aggregation, we constructed a Recombinant Inbred Line (RIL) panel derived from a cross between genetically divergent strains C. elegans NL5901 and SCH4856, both harboring the human αS gene. As a first step to discover genetic modifiers 70 αS-RILs were measured for whole-genome gene expression and expression quantitative locus analysis (eQTL) were mapped. We detected multiple eQTL hot-spots, many of which were located on Chromosome V. To confirm a causal locus, we developed Introgression Lines (ILs) that contain SCH4856 introgressions on Chromosome V in an NL5901 background. We detected 74 genes with an interactive effect between αS and the genetic background, including the human p38 MAPK homologue pmk-1 that has previously been associated with PD. Together, we present a unique αS-RIL panel for defining effects of natural genetic variation on αS pathology, which contributes to finding genetic modifiers of PD.
α-突触核蛋白（αS）的蛋白质聚集是帕金森病（PD）的遗传和神经病理学标志。对模式线虫秀丽隐杆线虫的研究表明，αS聚集的变化取决于遗传背景。然而，哪些基因和遗传修饰因子导致αS病理学的个体差异仍不清楚。为了研究αS聚集的基因型-表型关系，我们构建了一个重组自交系（RIL）群体，该群体来源于遗传差异较大的秀丽隐杆线虫品系NL5901和SCH4856之间的杂交，这两个品系都携带人类αS基因。作为发现遗传修饰因子的第一步，我们对70个αS-RIL进行了全基因组基因表达测量，并绘制了表达定量位点分析（eQTL）图谱。我们检测到多个eQTL热点，其中许多位于第五条染色体上。为了确认一个因果位点，我们开发了导入系（ILs），这些导入系在NL5901背景下的第五条染色体上含有SCH4856的导入片段。我们检测到74个基因在αS和遗传背景之间存在相互作用，其中包括先前与PD相关的人类p38丝裂原活化蛋白激酶同源物pmk-1。我们共同展示了一个独特的αS-RIL群体，用于定义自然遗传变异对αS病理学的影响，这有助于找到PD的遗传修饰因子。
