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Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease

1
Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza IA2 IIS Aragón, 50013 Zaragoza, Spain
2
ATLAS Molecular Pharma S.L., Parque tecnológico de Bizkaia, 48160 Derio, Spain
3
Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
4
Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, 28049 Madrid, Spain
5
Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain
6
IKERBasque Basque Foundation for Science, 48009 Bilbao, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to the experimental part of this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(1), 465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010465
Received: 13 November 2020 / Revised: 30 December 2020 / Accepted: 31 December 2020 / Published: 5 January 2021
(This article belongs to the Section Molecular Neurobiology)
Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrPC to its abnormal and misfolded isoform PrPSc is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion diseases, the mechanisms that trigger the formation of PrPSc in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrPSc 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 UbG76V-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 UbG76V-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. View Full-Text
Keywords: ER stress; endoplasmic reticulum; UPS impairment; proteasome; prions ER stress; endoplasmic reticulum; UPS impairment; proteasome; prions
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MDPI and ACS Style

Otero, A.; Betancor, M.; Eraña, H.; Fernández Borges, N.; Lucas, J.J.; Badiola, J.J.; Castilla, J.; Bolea, R. Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease. Int. J. Mol. Sci. 2021, 22, 465. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010465

AMA Style

Otero A, Betancor M, Eraña H, Fernández Borges N, Lucas JJ, Badiola JJ, Castilla J, Bolea R. Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease. International Journal of Molecular Sciences. 2021; 22(1):465. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010465

Chicago/Turabian Style

Otero, Alicia, Marina Betancor, Hasier Eraña, Natalia Fernández Borges, José J. Lucas, Juan J. Badiola, Joaquín Castilla, and Rosa Bolea. 2021. "Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease" International Journal of Molecular Sciences 22, no. 1: 465. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010465

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