1. Medicine
  2. Neuroscience
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PMCA generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

  1. Edoardo Bistaffa
  2. Alba Marín Moreno
  3. Juan Carlos Espinosa
  4. Chiara Maria Giulia De Luca
  5. Federico Angelo Cazzaniga
  6. Sara Maria Portaleone
  7. Luigi Celauro
  8. Giuseppe Legname
  9. Giorgio Giaccone
  10. Juan Maria Torres
  11. Fabio Moda  Is a corresponding author
  1. Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy
  2. Centro de Investigación en Sanidad Animal (CISA-INIA), Spain
  3. ASST Santi Paolo e Carlo Università Degli Studi di Milano, Italy
  4. Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Italy
Research Article
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Cite this article as: eLife 2021;10:e65311 doi: 10.7554/eLife.65311

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

  1. Edoardo Bistaffa

    Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Alba Marín Moreno

    Centro de Investigación en Sanidad Animal (CISA-INIA), Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos (Madrid), Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Juan Carlos Espinosa

    Centro de Investigación en Sanidad Animal (CISA-INIA), Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos (Madrid), Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6719-9902
  4. Chiara Maria Giulia De Luca

    Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Federico Angelo Cazzaniga

    Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Sara Maria Portaleone

    Department of Health Sciences, Otolaryngology Unit, ASST Santi Paolo e Carlo Università Degli Studi di Milano, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Luigi Celauro

    Department of Neuroscience, Laboratory of Prion Biology, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Giuseppe Legname

    Department of Neuroscience, Laboratory of Prion Biology, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Trieste, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Giorgio Giaccone

    Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Juan Maria Torres

    Centro de Investigación en Sanidad Animal (CISA-INIA), Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos (Madrid), Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0443-9232
  11. Fabio Moda

    Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
    For correspondence
    Fabio.Moda@istituto-besta.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2820-9880

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

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

Publication history

  1. Received: November 30, 2020
  2. Accepted: April 13, 2021
  3. Accepted Manuscript published: April 14, 2021 (version 1)
  4. 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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Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Eyad A Qunaibi et al.
    Research Article Updated

    Background:

    Vaccine hesitancy can limit the benefits of available vaccines in halting the spread of COVID-19 pandemic. Previously published studies paid little attention to Arab countries, which has a population of over 440 million. In this study, we present the results of the first large-scale multinational study that measures vaccine hesitancy among Arab-speaking subjects.

    Methods:

    An online survey in Arabic was conducted from 14 January 2021 to 29 January 2021. It consisted of 17 questions capturing demographic data, acceptance of COVID-19 vaccine, attitudes toward the need for COVID-19 vaccination and associated health policies, and reasons for vaccination hesitancy. R software v.4.0.2 was used for data analysis and visualization.

    Results:

    The survey recruited 36,220 eligible participants (61.1% males, 38.9% females, mean age 32.6 ± 10.8 years) from all the 23 Arab countries and territories (83.4%) and 122 other countries (16.6%). Our analysis shows a significant rate of vaccine hesitancy among Arabs in and outside the Arab region (83% and 81%, respectively). The most cited reasons for hesitancy are concerns about side effects and distrust in health care policies, vaccine expedited production, published studies and vaccine producing companies. We also found that female participants, those who are 30–59 years old, those with no chronic diseases, those with lower level of academic education, and those who do not know the type of vaccine authorized in their countries are more hesitant to receive COVID-19 vaccination. On the other hand, participants who regularly receive the influenza vaccine, health care workers, and those from countries with higher rates of COVID-19 infections showed more vaccination willingness. Interactive representation of our results is posted on our project website at https://mainapp.shinyapps.io/CVHAA.

    Conclusions:

    Our results show higher vaccine hesitancy and refusal among Arab subjects, related mainly to distrust and concerns about side effects. Health authorities and Arab scientific community have to transparently address these concerns to improve vaccine acceptance.

    Funding:

    This study received no funding.

    1. Medicine
    Melanie Castro-Mollo et al.
    Research Article Updated

    Background:

    Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis.

    Methods:

    To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe-/- mouse model as well as β–thalassemic (Hbbth3/+) mice with systemic loss of ERFE expression. In additional, we employ comprehensive skeletal phenotyping analyses as well as functional assays in vitro to address mechanistically the function of ERFE in bone.

    Results:

    We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe-/- mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe loss in Hbbth3/+mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss.

    Conclusions:

    Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in β–thalassemia.

    Funding:

    YZG acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to YZG and DK095112 to RF, SR, and YZG). MZ acknowledges the support of the National Institute on Aging (U19 AG60917) and NIDDK (R01 DK113627). TY acknowledges the support of the National Institute on Aging (R01 AG71870). SR acknowledges the support of NIDDK (R01 DK090554) and Commonwealth Universal Research Enhancement (CURE) Program Pennsylvania.