Acute Neurotoxicity Models of Prion Disease

Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrPC) into disease-associated conformers (PrPSc) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterisation of PrPSc species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease pathobiology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time consuming, and it can be problematic to clearly discern evidence of direct PrPSc neurotoxicity in the overall context of pathogenesis. In vitro models in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic and overall there remains a relative paucity of validated, biologically-relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we overview the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies.