Our research focuses on probing the pathogenesis of tauopathy. Tauopathy is a category of diseases of which the pathogenesis processes are all related to abnormal tau protein aggregation, which includes Alzheimer’s diseases and various parkinsonisms. Tau protein normally associates with microtubules to stabilize their structure, but it could undergo complex posttranslational modifications, causing its detachment from microtubules and forming aggregates under pathological conditions. Using Drosophila to expressing different human tau isoforms mimicking different posttranslational modifications, I could investigate which modifications are critical for modulating the protein’s toxicity and provide insights to some unsolved questions related to the posttranslational modifications of Tau. This study may help to pave the road for therapeutic development.