Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
Abstract Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous m...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-09-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01640-8 |
| _version_ | 1797451121478860800 |
|---|---|
| author | Hasier Eraña Carlos M. Díaz-Domínguez Jorge M. Charco Enric Vidal Ezequiel González-Miranda Miguel A. Pérez-Castro Patricia Piñeiro Rafael López-Moreno Cristina Sampedro-Torres-Quevedo Leire Fernández-Veiga Juan Tasis-Galarza Nuria L. Lorenzo Aileen Santini-Santiago Melisa Lázaro Sandra García-Martínez Nuno Gonçalves-Anjo Maitena San-Juan-Ansoleaga Josu Galarza-Ahumada Eva Fernández-Muñoz Samanta Giler Mikel Valle Glenn C. Telling Mariví Geijó Jesús R. Requena Joaquín Castilla |
| author_facet | Hasier Eraña Carlos M. Díaz-Domínguez Jorge M. Charco Enric Vidal Ezequiel González-Miranda Miguel A. Pérez-Castro Patricia Piñeiro Rafael López-Moreno Cristina Sampedro-Torres-Quevedo Leire Fernández-Veiga Juan Tasis-Galarza Nuria L. Lorenzo Aileen Santini-Santiago Melisa Lázaro Sandra García-Martínez Nuno Gonçalves-Anjo Maitena San-Juan-Ansoleaga Josu Galarza-Ahumada Eva Fernández-Muñoz Samanta Giler Mikel Valle Glenn C. Telling Mariví Geijó Jesús R. Requena Joaquín Castilla |
| author_sort | Hasier Eraña |
| collection | DOAJ |
| description | Abstract Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrPC) into the pathogenic isoform (PrPSc). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process. |
| first_indexed | 2024-03-09T14:50:20Z |
| format | Article |
| id | doaj.art-63c13fcaea6249e3a04b3b8cea76b3ad |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-09T14:50:20Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-63c13fcaea6249e3a04b3b8cea76b3ad2023-11-26T14:31:56ZengBMCActa Neuropathologica Communications2051-59602023-09-0111113010.1186/s40478-023-01640-8Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generationHasier Eraña0Carlos M. Díaz-Domínguez1Jorge M. Charco2Enric Vidal3Ezequiel González-Miranda4Miguel A. Pérez-Castro5Patricia Piñeiro6Rafael López-Moreno7Cristina Sampedro-Torres-Quevedo8Leire Fernández-Veiga9Juan Tasis-Galarza10Nuria L. Lorenzo11Aileen Santini-Santiago12Melisa Lázaro13Sandra García-Martínez14Nuno Gonçalves-Anjo15Maitena San-Juan-Ansoleaga16Josu Galarza-Ahumada17Eva Fernández-Muñoz18Samanta Giler19Mikel Valle20Glenn C. Telling21Mariví Geijó22Jesús R. Requena23Joaquín Castilla24Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkIRTA, Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCIMUS Biomedical Research Institute and Department of Medical Sciences, University of Santiago de Compostela-IDISCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkIRTA, Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB)Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkPrion Research Center (PRC), Colorado State UniversityAnimal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkCIMUS Biomedical Research Institute and Department of Medical Sciences, University of Santiago de Compostela-IDISCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology ParkAbstract Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrPC) into the pathogenic isoform (PrPSc). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process.https://doi.org/10.1186/s40478-023-01640-8PrionTransmissible spongiform encephalopathiesSpontaneous misfoldingStrain |
| spellingShingle | Hasier Eraña Carlos M. Díaz-Domínguez Jorge M. Charco Enric Vidal Ezequiel González-Miranda Miguel A. Pérez-Castro Patricia Piñeiro Rafael López-Moreno Cristina Sampedro-Torres-Quevedo Leire Fernández-Veiga Juan Tasis-Galarza Nuria L. Lorenzo Aileen Santini-Santiago Melisa Lázaro Sandra García-Martínez Nuno Gonçalves-Anjo Maitena San-Juan-Ansoleaga Josu Galarza-Ahumada Eva Fernández-Muñoz Samanta Giler Mikel Valle Glenn C. Telling Mariví Geijó Jesús R. Requena Joaquín Castilla Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation Acta Neuropathologica Communications Prion Transmissible spongiform encephalopathies Spontaneous misfolding Strain |
| title | Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| title_full | Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| title_fullStr | Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| title_full_unstemmed | Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| title_short | Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| title_sort | understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation |
| topic | Prion Transmissible spongiform encephalopathies Spontaneous misfolding Strain |
| url | https://doi.org/10.1186/s40478-023-01640-8 |
| work_keys_str_mv | AT hasiererana understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT carlosmdiazdominguez understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT jorgemcharco understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT enricvidal understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT ezequielgonzalezmiranda understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT miguelaperezcastro understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT patriciapineiro understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT rafaellopezmoreno understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT cristinasampedrotorresquevedo understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT leirefernandezveiga understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT juantasisgalarza understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT nuriallorenzo understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT aileensantinisantiago understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT melisalazaro understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT sandragarciamartinez understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT nunogoncalvesanjo understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT maitenasanjuanansoleaga understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT josugalarzaahumada understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT evafernandezmunoz understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT samantagiler understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT mikelvalle understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT glennctelling understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT marivigeijo understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT jesusrrequena understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration AT joaquincastilla understandingthekeyfeaturesofthespontaneousformationofbonafideprionsthroughanovelmethodologythatenablestheirswiftandconsistentgeneration |