Innovative method for creating new infectious prions: Advancing in the battle against neurodegenerative diseases

A collaborative international study, led by researchers at CIC bioGUNE – member of BRTA – and CIBERINFEC, has achieved a crucial milestone in the fight against prion diseases by developing a groundbreaking technology that enables the spontaneous generation of hundreds of new infectious prions.

The novel method, published in the scientific journal Nature Communications, enhance the understanding of the underlying mechanisms of prion diseases such as Creutzfeldt-Jakob disease or Fatal Familial Insomnia in humans – devastating and currently incurable illnesses.

Prion diseases, such as Creutzfeldt-Jakob disease or Fatal Familial Insomnia in humans, and mad cow disease in animals, result from the aberrant conversion of cellular prion protein (PrPC) into its pathogenic form (PrPSc or prion). However, the precise details of this conversion process remain largely unknown, limiting our ability to predict future outbreaks or potential transmission events between species.

The newly developed method, named "Protein Misfolding Shaking Amplification (PMSA)," enables the consistent and efficient generation of de novo prions in a test tube. Researchers applied this method to study over 380 prion proteins from various mammals, allowing them to classify them based on their propensity to acquire the pathogenic form and their structural variability.

This advancement represents a significant improvement over previous techniques, which exhibited greater variability and were only applied to proteins from a few model species. The publication, in addition to providing valuable insights into the factors determining prion infectivity, demonstrated the method's ability to generate prions from a wide variety of mammalian species. By inoculating these prions into highly susceptible animal models, researchers confirmed their infectious nature, validating the authenticity of in vitro generated prions and their utility as disease models.

The study offers a valuable tool for future research and clinical applications through the creation of a comprehensive database of prion protein variants, called "PrPdex". This database showcases the ability of each of these proteins to transform into an infectious prion, along with detailed information on their biophysical characteristics. This will aid the scientific community in accelerating the development of new diagnostic techniques and therapies targeting these diseases. Therefore, given its potential to unlock new insights into prion diseases and their impact on human and animal health, this study represents a significant step forward in the battle against these devastating neurodegenerative diseases.

This study has involved the participation of researchers from the Prion Research Lab, led by Ikerbasque Research Professor Joaquín Castilla, at CIC bioGUNE, in collaboration with researchers from Neiker, IRTA-CReSA, IIS Bioaraba, and Colorado State University. This breakthrough will contribute to a better understanding of the underlying mechanisms of prion diseases, potentially having significant implications for the future diagnosis and treatment of these neurodegenerative diseases.

Reference: Hasier Eraña, Cristina Sampedro-Torres-Quevedo, Jorge M. Charco, Carlos M. Díaz-Domínguez, Francesca Peccati, Maitena San-Juan-Ansoleaga, Enric Vidal, Nuno Gonçalves-Anjo, Miguel A. Pérez-Castro, Ezequiel González-Miranda, Patricia Piñeiro, Leire Fernández-Veiga, Josu Galarza-Ahumada, Eva Fernández-Muñoz, Guiomar Perez de Nanclares, Glenn Telling, Mariví Geijo, Gonzalo Jiménez-Osés and Joaquín Castilla. A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions. Nature Communications. DOI: 10.1038/s41467-024-46360-2.

About CIBERINFEC

The Consortium of Biomedical Network Research Centers (CIBER) is a public research consortium created on the initiative of the Instituto de Salud Carlos III / Carlos III Health Institute, of the Ministry of Science and Innovation, to further research of excellence in biomedicine and health sciences conducted within the National Health System and the Science and Technology System. The scientific program of the CIBER is organized around 13 thematic areas of research, including the area of Infectious Diseases (CIBERINFEC).

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About Ikerbasque

Ikerbasque - Basque Foundation for Science - is the result of an initiative by the Department of Education of the Basque Government to reinforce the commitment to scientific research by attracting, recovering, and consolidating excellent researchers from around the world. Currently, it is a consolidated organization with 290 researchers working in various fields of knowledge.

About BRTA

BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 12 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Lortek, Neiker, Tecnalia, Tekniker and Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.

BRTA has a workforce of 3,500 professionals, executes 22% of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.