PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
- Centro de Investigación en Sanidad Animal (CISA-INIA), Spain
- ASST Santi Paolo e Carlo Università Degli Studi di Milano, Italy
- Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Italy
Abstract
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).
Data availability
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Author details
Juan Carlos Espinosa
Funding
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.
Ethics
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).
Reviewing Editor
- J Paul Taylor, St Jude Children's Research Hospital, United States
Publication history
- 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)
Copyright
© 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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PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice
eLife 10:e65311.
https://doi.org/10.7554/eLife.65311
Further reading
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The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown.
Methods:
Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on >200 immune-cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls.
Results:
Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation.
Conclusions:
This study provides new insights into the genetic factors that affect immunological responses in T1D.
Funding:
This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).
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Background:
Deep brain stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MERs) or local field potential recordings can be used to extend neuroanatomical information (defined by MRI) with neurophysiological activity patterns recorded from micro- and macroelectrodes probing the surgical target site. Currently, these two sources of information (imaging vs. electrophysiology) are analyzed separately, while means to fuse both data streams have not been introduced.
Methods:
Here, we present a tool that integrates resources from stereotactic planning, neuroimaging, MER, and high-resolution atlas data to create a real-time visualization of the implant trajectory. We validate the tool based on a retrospective cohort of DBS patients (N = 52) offline and present single-use cases of the real-time platform.
Results:
We establish an open-source software tool for multimodal data visualization and analysis during DBS surgery. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present examples that demonstrate the functionality of the tool.
Conclusions:
This novel software platform for multimodal data visualization and analysis bears translational potential to improve accuracy of DBS surgery. The toolbox is made openly available and is extendable to integrate with additional software packages.
Funding:
Deutsche Forschungsgesellschaft (410169619, 424778381), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti), National Institutes of Health (2R01 MH113929), and Foundation for OCD Research (FFOR).
