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

eLife

Sara Maria Portaleone¹  Alba Marín-Moreno²  Juan Maria Torres²  Juan Carlos Espinosa²  Giorgio Giaccone³  Fabio Moda³  Edoardo Bistaffa³  Federico Angelo Cazzaniga³  Chiara Maria Giulia De Luca⁴  Giuseppe Legname⁵  Luigi Celauro⁵ 

[1] ASST Santi Paolo e Carlo, Department of Health Sciences, Otolaryngology Unit, Università Degli Studi di Milano, Milan, Italy;Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain;Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology 5 and Neuropathology, Milan, Italy;Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology 5 and Neuropathology, Milan, Italy;Scuola Internazionale Superiore di Studi Avanzati (SISSA), Department of Neuroscience, Laboratory of Prion Biology, Trieste, Italy;Scuola Internazionale Superiore di Studi Avanzati (SISSA), Department of Neuroscience, Laboratory of Prion Biology, Trieste, Italy;

关键词: fatal familial insomnia;    olfactory mucosa;    protein misfolding cyclic amplification;    transmission studies;    neurodegeneration;    prion;    Mouse;   

DOI  :  10.7554/eLife.65311

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Background: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).Methods: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.Results: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.Conclusions:Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.Funding: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).

【 授权许可】

CC BY