Experimental models to study prion disease pathogenesis and identify potential therapeutic compounds

•Cell-free prion replication assays promise to speed up the drug discovery process.•Astrocytes derived from human iPS cells are susceptible to human prions.•Prion-infected organotypic brain slices recapitulate prion neuropathology.•Drosophila melanogaster expressing ovine PrP can be infected with scrapie prions.•Transgenic PrP mice are valuable models for preclinical drug assessment. Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening platforms and preclinical models that recapitulate key molecular and pathological features of the disease. Innovative experimental tools have been developed over the last few years that might facilitate drug discovery, including cell-free prion replication assays and prion-infected flies. However, there is still room for improvement. Animal models of genetic prion disease are few, and only partially recapitulate the complexity of the human disorder. Moreover, we still lack a human cell culture model suitable for high-content anti-prion drug screening. This review provides an overview of the models currently used in prion research, and discusses their promise and limitations for drug discovery.