Genetically engineered cellular models of prion propagation

Abstract

For over three decades, cultured cells have been a useful tool for dissecting the molecular details of prion replication and the identification of candidate therapeutics for prion disease. A major issue limiting the translatability of these studies has been the inability to reliably propagate disease-relevant, non-mouse strains of prions in cells relevant to prion pathogenesis. In recent years, fueled by advances in gene editing technology, it has become possible to propagate prions from hamsters, cervids, and sheep in immortalized cell lines originating from the central nervous system. In particular, the use of CRISPR-Cas9-mediated gene editing to generate versions of prion-permissive cell lines that lack endogenous PrP expression has provided a blank canvas upon which re-expression of PrP leads to species-matched susceptibility to prion infection. When coupled with the ability to propagate prions in cells or organoids derived from stem cells, these next-generation cellular models should provide an ideal paradigm for identifying small molecules and other biological therapeutics capable of interfering with prion replication in animal and human prion disorders. In this review, we summarize recent advances that have widened the spectrum of prion strains that can be propagated in cultured cells and cutting-edge tissue-based models.