Rodent models for prion diseases

Abstract

-Until today most prion strains can only be propagated and the infectivity content assayed by experimentally challenging conventional or transgenic animals. Robust cell culture systems are not available for any of the natural and only for a few of the experimental prion strains. Moreover, the pathogenesis of different transmissible spongiform encephalopathies (TSE) can be analysed systematically by using experimentally infected animals. While, in the beginning, animals belonging to the natural host species were used, more and more rodent model species have been established, mostly due to practical reasons. Nowadays, most of these experiments are performed using highly susceptible transgenic mouse lines expressing cellular prion proteins, PrP, from a variety of species like cattle, sheep, goat, cervidae, elk, hamster, mouse, mink, pig, and man. In addition, transgenic mice carrying specific mutations or polymorphisms have helped to understand the molecular pathomechanisms of prion diseases. Transgenic mouse models have been utilised to investigate the physiological role of PrP C , molecular aspects of species barrier effects, the cell specificity of the prion propagation, the role of the PrP glycosylation, the mechanisms of the prion spread, the neuropathological roles of PrP C and of its abnormal isoform PrP D (D for disease) as well as the function of PrP Doppel. Transgenic mouse models have also been used for mapping of PrP regions involved in or required for the PrP conversion and prion replication as well as for modelling of familial forms of human prion diseases.

Atypical Transmissible Spongiform Encephalopathies in Ruminants: A Challenge for Disease Surveillance and Control

“…Transgenic mouse models overcome such limitations; these are mice that (over-) express heterologous PrP c on a murine, PrP c -ablated, genetic background. 89 The TSE isolates that exhibit different disease phenotypes in the same experimental model are then considered to represent distinct TSE agents, also referred to as prion strains. However, because the nature of the pathogen is still under debate, it remains difficult to develop a mechanistic understanding of how prion-strain characteristics are encoded.…”

Approaches to investigating transmission of spongiform encephalopathies in domestic animals using BSE as an example

“…The role of hamsters, mice, the burgeoning range of murine transgenes and other models such as voles is a large subject in its own right, and is covered by Groschup and Buschmann in this special issue [44] and elsewhere [28,43]. In the past such models have been useful [12,13], but they also have limitations.…”

“…Transgenic mouse models which overexpress human PrP are also available, and they are highly susceptible to BSE [7,15,65,106] but these may not be a true indicator of susceptibility in humans. Detailed discussion of these models is outwith the scope of this paper and is covered in detail by Groschup and Buschmann in this special issue [44].…”

Assessing Transmissible Spongiform Encephalopathy Species Barriers with an <em>In Vitro</em> Prion Protein Conversion Assay

“…Mice expressing PrP C from heterologous species are also used for this type of study 8 . The costs associated with transgenic mouse production and protracted prion bioassays, as well as ethical considerations of animal use, are obstacles to experimental investigation of TSE species barriers.…”