Ezequiel Gonzalez Miranda
Ezequiel Gonzalez Miranda
Prion Research Lab
Address: Bizkaia Science and Technology Park, building 502, Derio (Bizkaia)

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders affecting both humans and animals. TSEs can be of genetic, sporadic or infectious origin. The infectious agent associated with TSEs, termed prion, appears to consist of a single protein, an abnormal conformer (PrPSc) of a natural host protein (PrPC), which propagates by converting host PrPC into a replica of itself. One of the characteristics of prions is their ability to infect some species and not others. This phenomenon is known as transmission barrier. Interestingly, prions occur in the form of different strains that show distinct biological and physicochemical properties, even though they are encoded by PrP with the same amino acid sequence, albeit in presumably different conformations. In general, the transmission barrier is expressed by an incomplete attack rate and long incubation times (time from the animal inoculation until the onset of the clinical signs) which become shorter after serial inoculation passages. Compelling evidence indicates that the transmission barriers are closely related to differences in PrP amino acid sequences between the donor and recipients of infection, as well as the prion strain conformation. Unfortunately, the molecular basis of the transmission barrier phenomenon and its relationship to prion strain conformations is currently unknown and we cannot predict the degree of a species barrier simply by comparing the prion proteins from two species.

We have conducted a series of experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique that mimics in vitro some of the fundamental steps involved in prion replication in vivo, albeit with accelerated kinetics. The in vitro generated prions possess key prion features, i.e., they are infectious in vivo and maintain their strain specificity. We have used PMCA to efficiently replicate a variety of prion strains from, among others, mice, hamsters, bank voles, deer, cattle, sheep, and humans. The correlation between in vivo data and our in vitro results suggest that PMCA is a valuable tool for assessing the strength of the transmission barriers between diverse species and for different prion strains; we are using the method to determine which amino acids in the PrPC sequence contribute to the strength of the transmission barrier. These studies are proving very useful in evaluating the potential risks to humans and animals, of not only established prion strains, but also new (atypical) strains. For example, while classical sheep scrapie is unable to cross the human transmission barrier in vitro, bovine spongiform encephalopathy (BSE) propagated in sheep does so efficiently. In addition, we have also generated prions that are infectious to species hitherto considered to be resistant to prion disease.


Latest Publications

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

Erana, H;Charco, JM;Gonzalez-Miranda, E;Garcia-Martinez, S;Lopez-Moreno, R;Perez-Castro, MA;Diaz-Dominguez, CM;Garcia-Salvador, A;Castilla, J



Dogs are resistant to prion infection, due to the presence of asparagine at position 163 of their prion protein

Vidal, E;Fernandez-Borges, N;Erana, H;Parra, B;Pintado, B;Sanchez-Martin, MA;Charco, JM;Ordonez, M;Perez-Castro, MA;Pumarola, M;Mathiason, CK;Mayoral, T;Castilla, J



Development of a new largely scalable in vitro prion propagation method for the production of infectious recombinant prions for high resolution structural studies

Erana, H;Charco, JM;Di Bari, MA;Diaz-Dominguez, CM;Lopez-Moreno, R;Vidal, E;Gonzalez-Miranda, E;Perez-Castro, MA;Garcia-Martinez, S;Bravo, S;Fernandez-Borges, N;Geijo, M;D'Agostino, C;Garrido, ...



Qualitative analysis of the social and family impact of human transmissible spongiform encephalopathies

Coca, JR;Sanz-Molina, L;Erana, H;Castilla, J



A Single Amino Acid Substitution, Found in Mammals with Low Susceptibility to Prion Diseases, Delays Propagation of Two Prion Strains in Highly Susceptible Transgenic Mouse Models

Otero, A;Hedman, C;Fernandez-Borges, N;Erana, H;Marin, B;Monzon, M;Sanchez-Martin, MA;Nonno, R;Badiola, JJ;Bolea, R;Castilla, J



Insights into the Bidirectional Properties of the Sheep-Deer Prion Transmission Barrier

Harrathi, C;Fernandez-Borges, N;Erana, H;Elezgarai, SR;Venegas, V;Charco, JM;Castilla, J

Molecular neurobiology


The Prion 2018 round tables (II): A beta, tau, alpha-synuclein horizontal ellipsis are they prions, prion-like proteins, or what?

Erana, H



Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria

Urquiza, P(Urquiza, Pedro);Lain, A(Lain, Ana);Sanz-Parra, A(Sanz-Parra, Arantza);Moreno, J(Moreno, Jorge);Bernardo-Seisdedos, G(Bernardo-Seisdedos, Ganeko);Dubus, P(Dubus, Pierre);Gonzalez, ...

Science translational medicine


An Amino Acid Substitution Found in Animals with Low Susceptibility to Prion Diseases Confers a Protective Dominant-Negative Effect in Prion-Infected Transgenic Mice

Otero, A(Otero, Alicia);Bolea, R(Bolea, Rosa);Hedman, C(Hedman, Carlos);Fernandez-Borges, N(Fernandez-Borges, Natalia);Marin, B(Marin, Belen);Lopez-Perez, O(Lopez-Perez, Oscar);Barrio, T(Barrio, ...

Molecular neurobiology


iPS Cell Cultures from a Gerstmann-Straussler-Scheinker Patient with the Y218N PRNP Mutation Recapitulate tau Pathology

Matamoros-Angles, A(Matamoros-Angles, Andreu);Gayosso, LM(Mayela Gayosso, Lucia);Richaud-Patin, Y(Richaud-Patin, Yvonne);di Domenico, A(di Domenico, Angelique);Vergara, C(Vergara, Cristina);Hervera, ...

Molecular neurobiology