PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

Edoardo Bistaffa,Luigi Celauro,Alba Marín-Moreno,Giuseppe Legname,Juan Carlos Espinosa,Fabio Moda,Juan Maria Torres,Chiara Maria Giulia De Luca,Federico Angelo Cazzaniga,Giorgio Giaccone,Sara Maria Portaleone

doi:10.7554/elife.65311

Abstract

Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA). In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology. All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate. Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious. This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

Highlights

Fatal Familial Insomnia (FFI) is a genetic prion disorder caused by the conformational conversion of the cellular form of the prion protein (PrPC) into an abnormally folded conformer, named prion or PrPSc, which acquires toxic properties and accumulates in the brain [1]
Conclusions: with some experimental constraints, we show that PrPSc present in olfactory mucosa (OM) of FFI patients is potentially infectious
All inocula were subjected to Western blot (Wb) analysis to evaluate the presence of PrPres (Figure 1)

Summary

Introduction

Fatal Familial Insomnia (FFI) is a genetic prion disorder caused by the conformational conversion of the cellular form of the prion protein (PrPC) into an abnormally folded conformer, named prion or PrPSc, which acquires toxic properties and accumulates in the brain [1]. In 1992, it was shown that the cause of the disease is an autosomal dominant mutation at codon 178 of the PrPC encoding gene (PRNP) resulting in aspartic acid (D) to asparagine (N) substitution (D178N) [2]. The presence of MV (FFID178N-129MV) is associated with longer disease duration Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA)

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Conclusion