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| Pàgina inicial > Articles > Articles publicats > Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions |
(ATLAS Molecular Pharma S. L.) (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal) (ATLAS Molecular Pharma S. L., Derio, Spain) (Basque Research and Technology Alliance. Center for Cooperative Research in Biosciences) (Basque Research and Technology Alliance. Center for Cooperative Research in Biosciences) (Basque Research and Technology Alliance. Center for Cooperative Research in Biosciences) (Basque Research and Technology Alliance. Center for Cooperative Research in Biosciences) (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal) (Basque Research and Technology Alliance. Center for Cooperative Research in Biosciences) (Basque Foundation for Science)
| Data: | 2025 |
| Resum: | Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrP C to PrP Sc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully mimics spontaneous prion misfolding using minimal components. By employing this PMSA methodology and introducing an isoleucine residue at position 108 in mouse PrP, we successfully generated recombinant murine prion strains with distinct biochemical and biological properties. Our study aimed to explore the influence of a polyanionic cofactor in modulating strain selection and infectivity in de novo -generated synthetic prions. These results not only validate PMSA as a robust method for generating diverse bona fide recombinant prions but also emphasize the significance of cofactors in shaping specific prion conformers capable of crossing species barriers. Interestingly, once these conformers are established, our findings suggest that cofactors are not necessary for their infectivity. This research provides valuable insights into the propagation and maintenance of the pathobiological features of cross-species transmissible recombinant murine prion and highlights the intricate interplay between cofactors and prion strain characteristics. Prion diseases are rare and complex neurodegenerative disorders that can occur spontaneously, through a poorly understood conformational or structural change of normal, physiological prion protein. This abnormally structured form, known as prion, acquires the capacity to induce the same transformation to surrounding prion proteins, leading to disease. In our study, we take advantage of a recently developed methodology that closely mimics this process in a test tube using extremely simple components. Applying this system and modifying a specific part of the mouse prion protein, we were able to generate different prion strains with unique characteristics spontaneously. This process is greatly enhanced using an additional molecule called cofactor, that has been proposed to affect the variability and infectivity (capacity to cause disease in an animal model) of these prions. Our findings show that while cofactors facilitate the spontaneous formation of prions and may influence their final characteristics, they are not necessary for their infectivity nor for their spontaneous formation. This research gives new insights into the role cofactors play in the spontaneous generation of prions and their behavior in animal models. |
| Ajuts: | Ministerio de Ciencia e Innovación PID2021-122201OB-C21 Ministerio de Ciencia e Innovación PID2021-1222010B-C22 Ministerio de Ciencia e Innovación PID2020-117465GB-I00 Instituto de Salud Carlos III AC21_2/00024 Ministerio de Ciencia e Innovación CEX2021-001136-S Instituto de Salud Carlos III PT23/00123 |
| Nota: | Altres ajuts: Interreg POCTEFA 2021-2027 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Publicat a: | PLOS pathogens, Vol. 21 (january 2025) , ISSN 1553-7374 |
