Genetic studies in model organisms, including Drosophila, have a rich history of fundamental insights in neuroscience, including the identification and functional dissection of genes important in human disease. The fly nervous system operates on the same fundamental biological principles as its human counterpart, and many neurotransmitter systems including dopamine, acetylcholine, glutamate, and GABA are conserved from flies to humans. In addition, the Drosophila and human genomes share substantial homology, and the majority of human disease genes are conserved in flies. Compared to mammalian model systems,Drosophila offers the power of rapid and high-throughput genetic analysis, with a generation time ten times faster than the mouse. Further, fly models have now been developed for investigating a variety of neurodegenerative diseases, and these systems have demonstrated their utility for genetic dissection of disease mechanisms (Shulman et al. 2003 ). For example, when expressed in the Drosophila brain, Tau protein—which forms neurofibrillary tangle pathology in AD—causes adult onset, progressive neurodegeneration, truncated lifespan and increased phosphorylation and aggregation of Tau, thereby recapitulating several key features of human disease (Wittman et al. 2001).
We have participated in a genetic screen to identify enhancers and suppressors of Tau neurotoxicity in flies, revealing a number of molecular pathways with roles in AD pathogenesis (Shulman and Feany 2003). More recently, we have developed and validated a strategy that leverages Drosophila genetics to enhance the power of human genetic studies (Shulman et al. 2011). Despite the promise of genome-wide association studies, discovered polymorphisms rarely definitively identify causal susceptibility genes, but instead highlight broad genomic regions. In a pilot study, we used the Tau transgenic flies for functional validation of results from a genome-wide scan for AD neuropathologic burden. In 6 out of 15 genomic regions, we successfully identified a candidate causal gene for the association, based on in vivo genetic interactions with Tau neurotoxicity. We have extended this strategy to consider 159 independent loci achieving significant (p<5x10-8) or suggestive (p<10-4) associations with AD from GWAS. Ten Drosophila genes, orthologous to candidate human AD susceptibility genes, were validated in our functional screen. For example, loss-of-function in cindr, the fly ortholog of human CD2AP, enhances both Tau-induced retinal toxicity and age-dependent neurodegeneration in the brain (Shulman et al., unpublished data). CD2AP/cindr is a regulator of actin dynamics, and several other validated genes further implicate cell-adhesion pathways converging on the cytoskeleton as important in Tau neurotoxicity and AD susceptibility.