Research Article: Inherited Prion Disease A117V Is Not Simply a Proteinopathy but Produces Prions Transmissible to Transgenic Mice Expressing Homologous Prion Protein

Date Published: September 26, 2013

Publisher: Public Library of Science

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


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.

Partial Text

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]. Prions exist in multiple strains which are thought to represent distinct polymeric forms of misfolded PrP which faithfully propagate by recruitment of host PrPC onto pre-existing seeds or fibrils (for review see [3]). Human prion diseases may occur sporadically, be acquired by infection with environmental prions, or be inherited as autosomal dominant conditions as a result of one of more than 30 different coding mutations in the human PrP gene (PRNP) [4]. The cause of neuronal dysfunction and death in prion disease is unclear but neurotoxicity may be uncoupled from infectivity suggesting that prions themselves may not be directly neurotoxic and other PrP species might be involved in mediating toxicity [3], [5], [6].

We have demonstrated that GSS A117V is indeed a transmissible condition and properly designated an inherited prion disease rather than simply a prion proteinopathy without generation of prions. Additionally, we report that classical PrPSc is detectable in PrP 117V transgenic mouse brain using suitable conditions. The inability to detect classical PrPSc in patient brain had led to the proposal that the A117V mutation may cause pathology principally via an alternative pathway, namely through an increase in C-terminal transmembrane PrP, designated CtmPrP, to the total exclusion of PrPSc[8]. It has also not been shown whether or not 117V-PrPC is convertible to PrPSc. Using appropriate transgenic models challenged with classical CJD prion isolates, we have demonstrated that, despite the observed transmission barrier to clinical disease which can be explained by the 117V mutation producing a partial transmission barrier, 117V PrPC is a competent substrate for conversion to PrPSc. Notably, the newly generated PrPSc assumes the stable strain properties of the exogenous PrPSc and is therefore readily detectable on immunoblots.




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