A Drosophila model for mechanistic investigation of tau protein spread

Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau in Alzheimers disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We find age-dependent tau spread into the brain, represented by detection of tau, but not GFP in the brain. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin or the kinase glycogen synthase kinase-3{beta} (GSK-3{beta}). Further work revealed that dynamin promotes tau uptake in recipient tissues, whereas GSK-3{beta} appears to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau trafficking components involved in the pathogenesis of neurodegenerative diseases. SUMMARY STATEMENTThe trafficking of toxic proteins in neurodegenerative disease is well-known but poorly understood. Our model will allow rapid and new insight into molecular mechanisms underlying this process.