PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice
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 J.M.T. and J.C.E.; A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02).
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Ministero della Salute (GR-2013-02355724)
- Fabio Moda
Ministero della Salute (Ricerca Corrente)
- Fabio Moda
MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015)
- Fabio Moda
Euronanomed III (Speedy)
- Fabio Moda
Spanish Ministerio de Economia y Competitividad (AGL2016-78054-R (AEI/FEDER,UE))
- Juan Maria Torres
INIA (Fellowship FPI-SGIT-2015-02)
- Alba Marín Moreno
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: We conducted animal experiments in accordance with the Code for Methods and Welfare Considerations in Behavioural Research with Animals (Directive 2010/63/EU) and made every effort to minimize suffering. Experiments developed in Centro de Investigación en Sanidad Animal-Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (Madrid, Spain) were evaluated by the Committee on the Ethics of Animal Experiments of the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria and approved by the General Directorate of the Madrid Community Government (permit no. PROEX 263-15)
Human subjects: Written informed consent for participation in research and all procedures for sample collection and experimental studies were in accordance with the 1964 Declaration of Helsinki and its later amendments and were approved by the Ethical Committee of "Fondazione IRCCS Istituto Neurologico Carlo Besta" (Milan, Italy).
- J Paul Taylor, St Jude Children's Research Hospital, United States
- Received: November 30, 2020
- Accepted: April 13, 2021
- Accepted Manuscript published: April 14, 2021 (version 1)
- Version of Record published: April 23, 2021 (version 2)
© 2021, Bistaffa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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