Prion-associated neurodegeneration causes both endoplasmic reticulum stress and proteasome impairment in a murine model of spontaneous disease

Otero, Alicia (Universidad de Zaragoza) ; Betancor, Marina (Universidad de Zaragoza) ; Eraña, Hasier ; Fernández Borges, Natalia ; Lucas, José Javier ; Badiola, Juan José (Universidad de Zaragoza) ; Castilla, Joaquín ; Bolea, Rosa (Universidad de Zaragoza)

Resumen: Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. Conversion of 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 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) coexpressing 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. 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.

Idioma: Inglés

DOI: 10.3390/ijms22010465

Año: 2021

Publicado en: International Journal of Molecular Sciences 22, 1 (2021), Art. 465 [21 pp.]
ISSN: 1661-6596

Factor impacto JCR: 6.208 (2021)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 69 / 297 = 0.232 (2021) - Q1 - T1
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 50 / 180 = 0.278 (2021) - Q2 - T1

Factor impacto CITESCORE: 6.9 - Computer Science (Q1) - Chemical Engineering (Q1) - Medicine (Q1) - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 1.176 - Computer Science Applications (Q1) - Inorganic Chemistry (Q1) - Spectroscopy (Q1) - Organic Chemistry (Q1) - Physical and Theoretical Chemistry (Q1) - Molecular Biology (Q1)

Financiación: info:eu-repo/grantAgreement/EUR/INTERREG-POCTEFA/EFA-148-16 REDPRION
Financiación: info:eu-repo/grantAgreement/EUR/INTERREG-V-A-POCTEFA-2014-2020
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/RTI2018-096322-B-I00
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SEV-2016-0644

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Sanidad Animal (Dpto. Patología Animal)