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<sup>C</sup> to its abnormal and misfolded isoform PrP<sup>Sc</sup> is the main event in the pathogenesis of prion dise...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/465 |
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| author | Alicia Otero Marina Betancor Hasier Eraña Natalia Fernández Borges José J. Lucas Juan José Badiola Joaquín Castilla Rosa Bolea |
| author_facet | Alicia Otero Marina Betancor Hasier Eraña Natalia Fernández Borges José J. Lucas Juan José Badiola Joaquín Castilla Rosa Bolea |
| author_sort | Alicia Otero |
| collection | DOAJ |
| 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<sup>C</sup> to its abnormal and misfolded isoform PrP<sup>Sc</sup> 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<sup>Sc</sup> in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrP<sup>Sc</sup> 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<sup>G76V</sup>-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<sup>G76V</sup>-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. |
| first_indexed | 2024-03-10T13:27:47Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:27:47Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-219f7b12519f496e9a0e9089477f311e2023-11-21T08:36:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122146510.3390/ijms22010465Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous DiseaseAlicia Otero0Marina Betancor1Hasier Eraña2Natalia Fernández Borges3José J. Lucas4Juan José Badiola5Joaquín Castilla6Rosa Bolea7Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza IA2 IIS Aragón, 50013 Zaragoza, SpainCentro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza IA2 IIS Aragón, 50013 Zaragoza, SpainATLAS Molecular Pharma S.L., Parque tecnológico de Bizkaia, 48160 Derio, SpainCenter for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, SpainCentro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM, 28049 Madrid, SpainCentro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza IA2 IIS Aragón, 50013 Zaragoza, SpainCenter for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, SpainCentro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza IA2 IIS Aragón, 50013 Zaragoza, SpainPrion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrP<sup>C</sup> to its abnormal and misfolded isoform PrP<sup>Sc</sup> 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<sup>Sc</sup> in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrP<sup>Sc</sup> 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<sup>G76V</sup>-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<sup>G76V</sup>-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.https://www.mdpi.com/1422-0067/22/1/465ER stressendoplasmic reticulumUPS impairmentproteasomeprions |
| spellingShingle | Alicia Otero Marina Betancor Hasier Eraña Natalia Fernández Borges José J. Lucas Juan José Badiola Joaquín Castilla Rosa Bolea Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease International Journal of Molecular Sciences ER stress endoplasmic reticulum UPS impairment proteasome prions |
| 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 | ER stress endoplasmic reticulum UPS impairment proteasome prions |
| url | https://www.mdpi.com/1422-0067/22/1/465 |
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