Prion disease: experimental models and reality

Abstract

overview of the use of models of prion disease, how they have evolved alongside the scientific questions, and how advancements in technologies have pushed the boundaries of our understanding of prion biology. AbstractThe understanding of the pathogenesis and mechanisms of diseases requires a multidisciplinary approach, involving clinical observation, correlation to pathological processes, and modelling of disease mechanisms. It is an inherent challenge, and arguably impossible to generate model systems that can faithfully recapitulate all aspects of human disease. It is, therefore, important to be aware of the potentials and also the limitations of specific model systems. Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypothesis. Here, we evaluate and discuss model systems that were generated to understand clinical, pathological, genetic, biochemical, and epidemiological aspects of prion diseases. Whilst clinical research and studies on human tissue are an essential component of prion research, much of the understanding of the mechanisms governing transmission, replication, and toxicity comes from in vitro and in vivo studies. As with other neurodegenerative diseases caused by protein misfolding, the pathogenesis of prion disease is complex, full of conundra and contradictions. We will give here a historical Electronic supplementary material The online version of this article

Invited Review: The role of prion‐like mechanisms in neurodegenerative diseases

“…BSE cross-species transmission was first proven in wild-type mice (1988) and marmosets (1993) followed by transgenic mice, sheep, macaque and vole. A comprehensive review of transmission studies of prion diseases is in [124]. Recently, scrapie transmission after prolonged incubation periods has been demonstrated also in primate, cynomolgus macaque, which show high PrP protein homology to humans [125].…”

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

“…the rapidly progressive nature of these diseases and their low prevalence makes it impossible to gather enough cases that are not in the final stage, and iii. the animal models available for sporadic or genetic prion disease are scarce and, except for few examples, require infection to reproduce the prion disease for which they were designed [58]. Therefore, for acquired prion diseases and despite the phenotypic variability observed as a result of distinct administration routes, for the most socioeconomically relevant prion strains (scrapie, bovine spongiform encephalopathy (BSE), Chronic Wasting Disease (CWD), and vCJD), the initial sites of PrP Sc replication in the CNS are known as well as the kinetics of PrP Sc accumulation in the brain and in peripheral tissues in experimental and natural infections [15].…”

Transmissible human proteopathies: an expanding field

“…Since then, experimental transmission of inherited prion diseases has been attempted with varied success. A comprehensive overview of these research studies is given in [6].…”

“…The safety and transmission aspects of prion diseases have been extensively covered elsewhere and guidelines of best practice have been widely published by official bodies, such as the UK Department of Health and Public Health England (https://www.gov.uk/government/collections/creutzfeldtjakob-disease-cjd-guidance-data-and-analysis, accessed in September 2018) and this resource is continuously updated. Model systems of the transmission of prions have recently been published in a comprehensive review [6].…”