Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.

Emmanuel A Asante,Andrew Tomlinson,Jonathan D F Wadsworth,Tatiana Jakubcova,John Collinge,Sebastian Brandner,Asif Jeelani,Jacqueline M Linehan,Caroline Powell,Shyma Hamdan,Andrew Grimshaw,Michelle Smidak,David Westaway

doi:10.1371/journal.ppat.1003643

Abstract

Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals. However, some, and in particular an extensively studied type of Gerstmann-Sträussler-Scheinker syndrome (GSS) caused by a PRNP A117V mutation, are thought not to generate infectious prions and instead constitute prion proteinopathies with a quite distinct pathogenetic mechanism. Multiple attempts to transmit A117V GSS have been unsuccessful and typical protease-resistant PrP (PrPSc), pathognomonic of prion disease, is not detected in brain. Pathogenesis is instead attributed to production of an aberrant topological form of PrP, C-terminal transmembrane PrP (CtmPrP). Barriers to transmission of prion strains from one species to another appear to relate to structural compatibility of PrP in host and inoculum and we have therefore produced transgenic mice expressing human 117V PrP. We found that brain tissue from GSS A117V patients did transmit disease to these mice and both the neuropathological features of prion disease and presence of PrPSc was demonstrated in the brains of recipient transgenic mice. This PrPSc rapidly degraded during laboratory analysis, suggesting that the difficulty in its detection in patients with GSS A117V could relate to post-mortem proteolysis. We conclude that GSS A117V is indeed a prion disease although the relative contributions of CtmPrP and prion propagation in neurodegeneration and their pathogenetic interaction remains to be established.

Highlights

According to the widely accepted ‘‘protein-only’’ hypothesis [1], an abnormal isoform (PrPSc) of host-encoded cellular prion protein (PrPC) is the principal, and possibly the sole, constituent of the transmissible agent or prion [2]
Since prions may transmit more efficiently when the host’s normal prion protein amino acid sequence matches that of the infecting prion, we generated transgenic mice expressing human prion protein with the same amino acid sequence found in A117V Gerstmann-Straussler-Scheinker syndrome (GSS)
We found that brain tissue from GSS A117V patients could transmit disease to these mice, producing the typical brain lesions associated with GSS A117V

Summary

Introduction

According to the widely accepted ‘‘protein-only’’ hypothesis [1], an abnormal isoform (PrPSc) of host-encoded cellular prion protein (PrPC) is the principal, and possibly the sole, constituent of the transmissible agent or prion [2]. One inherited prion disease (IPD) in particular, associated with an alanine to valine substitution at residue 117 of PrP (A117V), has been proposed to cause neurodegeneration in the absence of PrPSc, with pathogenesis mediated by aberrant production of CtmPrP, a transmembrane form of PrP [7]. It has been proposed that PrPSc accumulation in other forms of prion disease may cause pathology by inducing the synthesis of CtmPrP de novo [8]. This aberrant topologic form of PrP has been hypothesised to cause neurologic dysfunction by disrupting the function of mahogunin, a cytosolic ubiquitin ligase whose loss causes spongiform neurodegeneration [9].

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