Drosophila wing is a high-throughput and versatile screening tool for Tau-mediated disease mechanisms and drug discovery.

Abstract

Tau protein contributes to microtubule stability, which is disrupted in Alzheimer's disease and other tauopathies. In these diseases, Tau molecules become hyperphosphorylated, misfolded and aggregated, propagating pathology across the brain. Studies dissecting disease mechanisms or screening disease-modifying therapies rely on animal models that unveil pathogenic events in vivo but also take several weeks or months to complete. Here, we describe a versatile experimental paradigm that yields results in days and yet offers all the advantages of a genetically tractable in vivo system: the Drosophila wing. Mimicking neurotoxicity, human Tau expression caused cell death in Drosophila wing disc, leading to quantifiable phenotypes in the adult wing. The neuroprotective peptide NAPVSIPQ ameliorated Tau toxicity in this system, validating it as a cost-effective drug-screening tool. Phenocopying adult neurons, Tau toxicity in the wing disc was exacerbated by simulating hyperphosphorylation and prevented by suppressing aggregation. Additionally, we showed that the wing disc can dissect disease mechanisms that underpin clinically relevant Tau variants. Thus, the Drosophila wing offers an in vivo experimental paradigm for fast and efficient exploration of disease mechanism and screening.