Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms

Neurodegenerative diseases like Alzheimer's-disease (AD) and Parkinson's-disease (PD) represent an increasing threat to human health. Despite progress in identification of several AD and PD related genes, the effect of alleles underlying protein misfolding in these diseases remains unclear. Given the molecular conservation in essential signalling between the model organism C. elegans and humans, transgenic worms that express aggregating proteins have been created for studying the onset and progression of these diseases and the functional alleles that affect them. For example, analysis of transgenic worms expressing the human synaptic protein alpha-synuclein, of which accumulation is causative of PD, have identified links between its proteotoxicity and insulin/insulin-like growth factor (IGF), mitochondrial dysfunction, and aging. The evolutionary forces drive genome generation, and natural variants show impacts on molecular and cellular processes, leading to complex organismal phenotypes in plants, worms, flies, rodents as well as humans. However, previous researches that solely rely on induced mutants in canonical N2 limit the ability to explore how naturally varying alleles alter signalling pathways, including investigation on protein misfolding disease pathological mechanisms. Our research aims to go beyond classical mutant screens on the genetic pathway analysis of complex traits, i.e. phenotypic differences among individuals, to also consider the allelic interactions in different genetic backgrounds. We have therefore introgressed the PD transgene (unc-54: α-Syn:YFP) into four different wild isolate genetic backgrounds. Analysis of life history in these new introgressed lines indicates that the transgene effects vary greatly depending on the background. This is a necessary and important step to generally understand the influence of natural variation of the genetic background on the disease progressing mechanism.