New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein

Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases is a natural resource that can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with new, robust phenotypes in brain neurons and the eye. Using comparable attP2 insertions, we demonstrate the heightened toxicity of human PrP compared to rodent PrP along with a specific interaction with the amyloid-β peptide. Using this new model, we started to uncover the intrinsic (sequence / structure) and extrinsic (interactions) factors regulating PrP toxicity. We describe PERK and ATF4as key cellular mechanism mediating the toxicity of human PrP and uncover a key new protective activity for 4E-BP, an ATF4 transcriptional target. Lastly, mutations in human PrP (N159D, D167S, N174S) show partial protective activity, revealing its high propensity to misfold into toxic conformations.