The common neurodegenerative disorders Alzheimer’s disease (AD) and Parkinson’s disease (PD) are both characterized by the accumulation and spread of protein aggregates through the nervous system. As in prion disorders, the protein aggregates that occur in AD and PD are believed to propagate by transfer of aggregate seeds to recipient cells, where the seeds serve as templates for conversion of their normally folded counterparts into aggregating forms. The spread of protein aggregates is accepted as an essential part of the pathogenesis of both AD and PD, yet none of the more than 100 loci that influence the risk of AD and PD are known to affect the spread of protein aggregates between tissues, and the underlying mechanisms are poorly understood. One reason for this gap in understanding is the scarcity of genetically tractable in vivo model systems for studying propagation and spread of aggregated tau and alpha-synuclein, two key aggregate-prone proteins in AD and PD. The goal of this pilot project grant is to develop a simple, modular, and highly tractable set of Drosophila models to study the spread of protein aggregation. First, we will create transgenic lines that will permit us to express multiple combinations of WT and mutant forms of tau and alpha-synuclein. We will then use these lines to express the WT forms of these proteins at low levels throughout the nervous system, while overexpressing WT or mutant forms of the same protein in a small subset of cells to initiate aggregation. Using epitope tags to distinguish the products of the transgenes, we will visualize and quantify the resulting spread of aggregates. This set of transgenic lines will facilitate rapid investigation of the effects of previously identified genetic risk factors and candidate cellular pathways on the spread of protein aggregates in neurodegenerative disease. Our system will thus advance understanding of the mechanisms underlying the spread of protein aggregates in AD and PD, which in turn may reveal new targets for therapeutic intervention in these common and debilitating disorders.