Abstract
Neurotoxicity of alpha-synuclein (aSyn) is a pathogenetic hallmark of synucleinopathies, including Parkinson’s diseases (PD). Only about 10% of diagnosed Parkinson’s disease (PD) have familial history with identified genetic variations, while pathogenetic triggers in sporadic forms of PD are largely unknown. Genome-wide association studies over recent years have revealed approximately 90 risk genetic loci associated with developed PD. To date, however, there is little to no functional validation of genes in these loci. In this study, we performed reverse genetic screening of some of these candidate risk genes, looking for modulated toxicity of aSyn in dopaminergic neurons of C. elegans. We generated C. elegans PD model expressing GFPtagged aSyn in dopaminergic neurons, which forms aSyn inclusions and triggers neurodegeneration in aged animals. Using RNA interference, we targeted C. elegans orthologs of 100 human risk genes for PD from the published GWAS loci and identified knockdown animals with exacerbated or alleviated aSyn-induced neurodegeneration. We show that several genes regulating calcium signalling modulated aSyn toxicity in dopaminergic neurons and conclude that the genes regulating import of calcium into mitochondria are potential therapeutic targets for PD.