Cargando…
Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease
Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrP(C) to its abnormal and misfolded isoform PrP(Sc) is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796520/ https://www.ncbi.nlm.nih.gov/pubmed/33466523 http://dx.doi.org/10.3390/ijms22010465 |
_version_ | 1783634701810925568 |
---|---|
author | Otero, Alicia Betancor, Marina Eraña, Hasier Fernández Borges, Natalia Lucas, José J. Badiola, Juan José Castilla, Joaquín Bolea, Rosa |
author_facet | Otero, Alicia Betancor, Marina Eraña, Hasier Fernández Borges, Natalia Lucas, José J. Badiola, Juan José Castilla, Joaquín Bolea, Rosa |
author_sort | Otero, Alicia |
collection | PubMed |
description | Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrP(C) to its abnormal and misfolded isoform PrP(Sc) is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion diseases, the mechanisms that trigger the formation of PrP(Sc) in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrP(Sc) can induce endoplasmic reticulum (ER) stress and proteasome impairment from the early stages of the prion disease. Both mechanisms lead to an increment of PrP aggregates in the secretory pathway, which could explain the pathogenesis of spontaneous prion diseases. Here, we investigate the role of ER stress and proteasome impairment during prion disorders in a murine model of spontaneous prion disease (TgVole) co-expressing the Ub(G76V)-GFP reporter, which allows measuring the proteasome activity in vivo. Spontaneously prion-affected mice showed a significantly higher accumulation of the PKR-like ER kinase (PERK), the ER chaperone binding immunoglobulin protein (BiP/Grp78), the ER protein disulfide isomerase (PDI) and the Ub(G76V)-GFP reporter than age-matched controls in certain brain areas. The upregulation of PERK, BiP, PDI and ubiquitin was detected from the preclinical stage of the disease, indicating that ER stress and proteasome impairment begin at early stages of the spontaneous disease. Strong correlations were found between the deposition of these markers and neuropathological markers of prion disease in both preclinical and clinical mice. Our results suggest that both ER stress and proteasome impairment occur during the pathogenesis of spontaneous prion diseases. |
format | Online Article Text |
id | pubmed-7796520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77965202021-01-10 Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease Otero, Alicia Betancor, Marina Eraña, Hasier Fernández Borges, Natalia Lucas, José J. Badiola, Juan José Castilla, Joaquín Bolea, Rosa Int J Mol Sci Article Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrP(C) to its abnormal and misfolded isoform PrP(Sc) is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion diseases, the mechanisms that trigger the formation of PrP(Sc) in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrP(Sc) can induce endoplasmic reticulum (ER) stress and proteasome impairment from the early stages of the prion disease. Both mechanisms lead to an increment of PrP aggregates in the secretory pathway, which could explain the pathogenesis of spontaneous prion diseases. Here, we investigate the role of ER stress and proteasome impairment during prion disorders in a murine model of spontaneous prion disease (TgVole) co-expressing the Ub(G76V)-GFP reporter, which allows measuring the proteasome activity in vivo. Spontaneously prion-affected mice showed a significantly higher accumulation of the PKR-like ER kinase (PERK), the ER chaperone binding immunoglobulin protein (BiP/Grp78), the ER protein disulfide isomerase (PDI) and the Ub(G76V)-GFP reporter than age-matched controls in certain brain areas. The upregulation of PERK, BiP, PDI and ubiquitin was detected from the preclinical stage of the disease, indicating that ER stress and proteasome impairment begin at early stages of the spontaneous disease. Strong correlations were found between the deposition of these markers and neuropathological markers of prion disease in both preclinical and clinical mice. Our results suggest that both ER stress and proteasome impairment occur during the pathogenesis of spontaneous prion diseases. MDPI 2021-01-05 /pmc/articles/PMC7796520/ /pubmed/33466523 http://dx.doi.org/10.3390/ijms22010465 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Otero, Alicia Betancor, Marina Eraña, Hasier Fernández Borges, Natalia Lucas, José J. Badiola, Juan José Castilla, Joaquín Bolea, Rosa Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title | Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title_full | Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title_fullStr | Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title_full_unstemmed | Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title_short | Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease |
title_sort | prion-associated neurodegeneration causes both endoplasmic reticulum stress and proteasome impairment in a murine model of spontaneous disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796520/ https://www.ncbi.nlm.nih.gov/pubmed/33466523 http://dx.doi.org/10.3390/ijms22010465 |
work_keys_str_mv | AT oteroalicia prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT betancormarina prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT eranahasier prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT fernandezborgesnatalia prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT lucasjosej prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT badiolajuanjose prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT castillajoaquin prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease AT bolearosa prionassociatedneurodegenerationcausesbothendoplasmicreticulumstressandproteasomeimpairmentinamurinemodelofspontaneousdisease |