IDENTIFICATION OF ALPHA-SYNUCLEIN DOMINANT MODIFIERS IN A DROSOPHILA MODEL OF NEURODEGENERATION

Abstract

Parkinson disease (PD) is the second most common neurodegeneration disease in the world. Our knowledge of the genetic factors underlying PD is incomplete. Using a Drosophila model of neurodegeneration, we conducted climbing screens and identified mutant lines that affect the climbing performance. The underlying mutations were mapped. Retina degeneration assay shows that 12 genes enhance the SNCA-induced neuronal degeneration in cell body and/or synapse. In 6 mutants, the enhanced neurodegeneration phenotype could be rescued by transgenic chromosome fragment containing the candidate gene. Human homologues of several candidate SNCA modifiers are located near the identified PD risk loci from GWAS, thus providing independent evidence to assign the correct PD-related gene at these loci. Our results support a model that part of the missing PD heritability is explained by epistasis of SNCA with a large number of pro-disease variants in other genes which act as SNCA modifiers.