Genome-wide genotype-phenotype associations in Drosophila for neurodegenerative disease pathway and drug target discovery.

The increase in life expectancy in the Western world has seen a growing number of individuals suffering from neurodegenerative disorders. Many of these disorders are associated with the accumulation of toxic protein species, such as amyloid beta (aß) peptides in Alzheimer’s disease (AD), microtubule-binding Tau in AD and frontotemporal lobe degeneration (FTLD), a-synuclein in Parkinson’s disease (PD), and TDP-43 in amyotrophic lateral sclerosis (ALS) and FTLD. Although familial forms of these disorders have been identified, the majority of cases are sporadic, with age being the most important risk factor. Nevertheless, available evidence supports a complex genetic nature that is not well understood. We propose to perform a systematic analysis of the effects of genome-wide genetic variants on disease severity and progression starting from defined disease-causing events to identify disease-relevant pathways and candidate drug targets. We propose to do this by using the Drosophila melanogaster Genetic Reference Panel, a newly developed resource to systematically interrogate genotype-phenotype relationships for any given trait. The goals are (1) to identify genetic factors that influence agerelated progression of disease-like phenotypes induced by neuronal expression of toxic protein species associated with AD, FTLD, ALS, CMT, polyglutamine disorders and PD and (2) to identify naturally occurring genetic variants that cause degeneration of the nervous system.