PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice.
fatal familial insomnia
medicine
mouse
neurodegeneration
neuroscience
olfactory mucosa
prion
protein misfolding cyclic amplification
transmission studies
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
14 04 2021
14 04 2021
Historique:
received:
30
11
2020
accepted:
13
04
2021
pubmed:
15
4
2021
medline:
14
9
2021
entrez:
14
4
2021
Statut:
epublish
Résumé
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).
Sections du résumé
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).
Identifiants
pubmed: 33851575
doi: 10.7554/eLife.65311
pii: 65311
pmc: PMC8064759
doi:
pii:
Substances chimiques
PrPSc Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero della Salute
ID : GR-2013-02355724
Organisme : Ministero della Salute
ID : Ricerca Corrente
Organisme : MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute
ID : BAND2015
Organisme : Euronanomed III
ID : Speedy
Organisme : Spanish Ministerio de Economia y Competitividad
ID : AGL2016-78054-R (AEI/FEDER,UE)
Organisme : INIA
ID : Fellowship FPI-SGIT-2015-02
Organisme : Euronanomed III
ID : SPEEDY
Organisme : Ministerio de Economía y Competitividad
ID : AGL2016-78054-R (AEI/FEDER,UE)
Informations de copyright
© 2021, Bistaffa et al.
Déclaration de conflit d'intérêts
EB, AM, JE, CD, FC, SP, LC, GL, GG, JT, FM No competing interests declared
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