Drosophila Models of Prion Diseases

Abstract Prion diseases encompass a heterogeneous group of fatal brain disorders associated with the accumulation of misfolded isoforms of the prion protein (PrP) in brain neurons. Modeling these diseases in rodent models in the laboratory have led to fundamental advances in our understanding of prion transmission and pathogenesis. Genetically tractable animal models such as the fruit fly Drosophila melanogaster have made significant contributions to neurodegenerative disorders, including prion diseases. When we wrote the original version of this chapter 9 years ago for the inaugural book series in 2013 (written in 2012), very little work had been done in Drosophila models expressing mammalian PrP. In fact, so little had been done that we included work on non-mammalian models of PrP biology and pathophysiology. Since then, the amount of work on Drosophila models has expanded considerably. Over the last 10 years, the number of transgenic fly models and their application has continued to grow. These recent models have addressed fundamental aspects of PrP function and physiology, mechanisms of neurotoxicity, identification of residues mediating PrP misfolding and toxicity, and progress on the development of prion bioassays for surveillance that can reduce the use of rodents for that purpose. This updated chapter describes the main advances in Drosophila models expressing mammalian PrP over the last 10 years.