Pathological modifications in the microtubule-associated protein Tau is a common characteristic observed in different neurological diseases, suggesting that analogous metabolic pathways might be similarly affected during neurodegeneration. To identify these molecules and mechanisms, we utilized Drosophila models of human Tau-mediated neurodegeneration to perform an RNA interference functional screening against genes considered to be implicated in the pathogenesis of different neurodegenerative disorders. We found that the downregulation of the Drosophila REEP1 homolog protein enhanced Tau toxicity with increased formation of insoluble aggregates. On the contrary, the overexpression of either the Drosophila or the human REEP1 protein was able to revert these phenotypes and promote neuronal resistance to ER stress. These studies identify a new function for the REEP1 protein in vivo and a novel cellular mechanism to prevent Tau toxicity.