Neurodegenerative diseases (NGDs), such as Alzheimer’s diseases (AD) and Parkinson’s diseases (PD), are characterized by progressive degeneration in the human nervous system. The effect of variants harboured in genetic background on diseases onset and progression has been identified in studies with either humans or other model organisms. The nematode C. elegans is one of the powerful models in which to study human complex diseases studies, e.g. NGDs, due to the high level of conservation of gene functions compared to humans. Researches with C. elegans largely relies on a single worm genotype – the laboratory N2 strain – limiting the ability to explore how naturally varying alleles alter pathological mechanisms in NGDs. Hence we focused on a C. elegans model of α-synuclein, of which aggregate formation (i.e. Lewy body) is the pathological hallmark of PD, and introduced five more different genetic backgrounds into this model. Life history phenotypic traits, including shortened lifespan, development delay, pumping arrest, and so on, together with the microarray-based gene expression analysis indicate that α-synuclein transgene effects vary greatly depending on the genetic background. Functional enrichment analysis reveals that the background genes which significantly responded to the α-synuclein-effect link to the developmental arrest, metabolic, and cellular repair mechanisms. Moreover, we also identified variable accumulated both protein aggregation and lipid contents in different genetic backgrounds. These results together suggest natural genetic variation appears to affect α-synuclein aggregation and proteotoxicity resulting in a variety of disease phenotypic outcomes. Furthermore, we performed eQTL mapping in the newly constructed panel of NL5901xSCH4856 recombinant inbred lines (RILs) harbouring the α-synuclein introgression. By detectable expression levels of the parental (N2&CB4856) genotypes of the RILs population, both cis- and trans-effects of variants were identified, which provides insight into the underlying genetic architecture of transcriptional phenotype in response to introgressed α-synuclein. Overall, these together highlights the importance of C. elegans' variable genetic backgrounds in human α-synuclein pathology studies. Especially, genetic variants present differential alterations in global gene expression in response to α-synuclein and/or proteotoxicity, which could not be readily observed in the N2 background. Despite still having inherent limitations, it is essential to consider the influence of natural variation in genetic background on the disease onset and progressing mechanism.