Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity
Protein misfolding is central to numerous neurodegenerative disorders, collectively known as proteinopathies, which include Alzheimer's disease, Parkinson's disease, and prion diseases, among others. In many cases, specific polymorphisms of the proteins associated with these diseases influ...
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002219 |
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| author | Carlos M. Díaz-Domínguez Hasier Eraña Francesca Peccati Enric Vidal Jorge M. Charco Cristina Sampedro-Torres-Quevedo Miguel A. Pérez-Castro Nuria L. Lorenzo Samanta Giler Glenn C. Telling Mariví Geijo Jesús R. Requena Gonzalo Jiménez-Osés Joaquín Castilla |
| author_facet | Carlos M. Díaz-Domínguez Hasier Eraña Francesca Peccati Enric Vidal Jorge M. Charco Cristina Sampedro-Torres-Quevedo Miguel A. Pérez-Castro Nuria L. Lorenzo Samanta Giler Glenn C. Telling Mariví Geijo Jesús R. Requena Gonzalo Jiménez-Osés Joaquín Castilla |
| author_sort | Carlos M. Díaz-Domínguez |
| collection | DOAJ |
| description | Protein misfolding is central to numerous neurodegenerative disorders, collectively known as proteinopathies, which include Alzheimer's disease, Parkinson's disease, and prion diseases, among others. In many cases, specific polymorphisms of the proteins associated with these diseases influence their misfolding. However, the precise ways in which these polymorphisms affect protein integrity and how they contribute to misfolding propensity remain unclear. In the case of prion diseases, they are caused by prions or PrPSc, the misfolded isoforms of the cellular prion protein (PrPC). Chronic Wasting Disease (CWD) is a prion disease that affects cervids and can exhibit lymphotropic properties, making it the most widespread proteinopathy. For that reason, cervid PrPs and their polymorphisms have been extensively studied. To better understand the role of these polymorphisms, we analyzed 45 cervid PrP variants to assess their effects on flexibility, stability, and spontaneous misfolding propensity.The cervid variants were expressed as recombinant PrP in E. coli and were analyzed for thermal stability using circular dichroism. Additionally, the rec-PrPs served as substrates for Protein Misfolding Shaking Amplification (PMSA), enabling assessment of each variant's spontaneous misfolding propensity. This process led to the formation of bona fide prions, as confirmed by inoculation of one of the resulting conformers into transgenic mice expressing bank vole PrP. In parallel, molecular dynamics simulations were conducted to analyze the structural flexibility of the variants. While differences in protein flexibility were observed, no correlation was detected among flexibility, thermal stability, and the observed variable spontaneous misfolding propensity, suggesting that these properties are independent parameters. |
| format | Article |
| id | doaj-art-bd0eb2d41de44854b2b3e7148984575f |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-bd0eb2d41de44854b2b3e7148984575f2025-08-20T03:32:23ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310700510.1016/j.nbd.2025.107005Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensityCarlos M. Díaz-Domínguez0Hasier Eraña1Francesca Peccati2Enric Vidal3Jorge M. Charco4Cristina Sampedro-Torres-Quevedo5Miguel A. Pérez-Castro6Nuria L. Lorenzo7Samanta Giler8Glenn C. Telling9Mariví Geijo10Jesús R. Requena11Gonzalo Jiménez-Osés12Joaquín Castilla13Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.; ATLAS Molecular Pharma S. L., Derio, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.IRTA. Programa de Sanitat Animal. Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia. Spain.; Unitat mixta d'Investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia. Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.; ATLAS Molecular Pharma S. L., Derio, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.CIMUS Biomedical Research Institute & Department of Medical Sciences, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.IRTA. Programa de Sanitat Animal. Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia. Spain.; Unitat mixta d'Investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Catalonia. Spain.Prion Research Center. Colorado State University, Fort Collins, USA.Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Derio, Spain.CIMUS Biomedical Research Institute & Department of Medical Sciences, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.; Corresponding author at: Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.Protein misfolding is central to numerous neurodegenerative disorders, collectively known as proteinopathies, which include Alzheimer's disease, Parkinson's disease, and prion diseases, among others. In many cases, specific polymorphisms of the proteins associated with these diseases influence their misfolding. However, the precise ways in which these polymorphisms affect protein integrity and how they contribute to misfolding propensity remain unclear. In the case of prion diseases, they are caused by prions or PrPSc, the misfolded isoforms of the cellular prion protein (PrPC). Chronic Wasting Disease (CWD) is a prion disease that affects cervids and can exhibit lymphotropic properties, making it the most widespread proteinopathy. For that reason, cervid PrPs and their polymorphisms have been extensively studied. To better understand the role of these polymorphisms, we analyzed 45 cervid PrP variants to assess their effects on flexibility, stability, and spontaneous misfolding propensity.The cervid variants were expressed as recombinant PrP in E. coli and were analyzed for thermal stability using circular dichroism. Additionally, the rec-PrPs served as substrates for Protein Misfolding Shaking Amplification (PMSA), enabling assessment of each variant's spontaneous misfolding propensity. This process led to the formation of bona fide prions, as confirmed by inoculation of one of the resulting conformers into transgenic mice expressing bank vole PrP. In parallel, molecular dynamics simulations were conducted to analyze the structural flexibility of the variants. While differences in protein flexibility were observed, no correlation was detected among flexibility, thermal stability, and the observed variable spontaneous misfolding propensity, suggesting that these properties are independent parameters.http://www.sciencedirect.com/science/article/pii/S0969996125002219CWDMisfoldingPolymorphismsPrionProteinopathyStability |
| spellingShingle | Carlos M. Díaz-Domínguez Hasier Eraña Francesca Peccati Enric Vidal Jorge M. Charco Cristina Sampedro-Torres-Quevedo Miguel A. Pérez-Castro Nuria L. Lorenzo Samanta Giler Glenn C. Telling Mariví Geijo Jesús R. Requena Gonzalo Jiménez-Osés Joaquín Castilla Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity Neurobiology of Disease CWD Misfolding Polymorphisms Prion Proteinopathy Stability |
| title | Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity |
| title_full | Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity |
| title_fullStr | Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity |
| title_full_unstemmed | Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity |
| title_short | Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity |
| title_sort | effect of primary structural variation on cervid prion protein in flexibility stability and spontaneous misfolding propensity |
| topic | CWD Misfolding Polymorphisms Prion Proteinopathy Stability |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002219 |
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