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Antonio Masone¹, Anna Grasso¹, Liliana Comerio¹

¹Laboratory of Prion Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.

Acta neuropathologica

|February 10, 2026

Resumen

Las enfermedades priónicas genéticas provienen del mal plegamiento de la proteína priónica mutante. Este estudio encontró que si bien la mutación D178N en ratones no crea priones infecciosos, la conversión in vitro produce nuevas cepas de priones con propiedades únicas.

Área de la Ciencia:

La neurociencia es la neurociencia.
Biología Molecular Biología Molecular
Genética La genética.

Sus antecedentes:

Las enfermedades priónicas genéticas implican la proteína priónica mal plegada (PrP) que forma el PrPSc. infeccioso.
Las mutaciones en PrP están relacionadas con diversos fenotipos de enfermedades y cepas priónicas.
Estudios anteriores mostraron que los ratones transgénicos con mutaciones D178N desarrollan enfermedades neurológicas pero no priones transmisibles.

Objetivo del estudio:

Para investigar si los ratones transgénicos que expresan mutaciones D178N generan priones infecciosos.
Para caracterizar las propiedades de los priones generados in vitro a partir de estos modelos de ratón.
Para comparar priones generados in vitro con el insomnio familiar fatal humano (FFI) y la enfermedad genética de Creutzfeldt-Jakob (CJD178).

Principales métodos:

Inoculación de ratones de banco con homogenatos cerebrales de ratones transgénicos.
Detección de priones mediante conversión inducida por temblores en tiempo real (RT-QuIC).
Conversión in vitro de PrP utilizando la amplificación cíclica de plegamiento erróneo de proteínas (PMCA) con semilla RML PrPSc.
Propagación en serie y caracterización de priones convertidos en ratones Tga20.

Principales resultados:

Los ratones transgénicos que expresaban mutaciones D178N no producían priones transmisibles, lo que fue confirmado por la inoculación de vole y el RT-QuIC.
La conversión in vitro generó priones RMLFFI y RMLCJD que se propagaron en ratones Tga20.
Estos priones generados in vitro mostraron una mala transmisibilidad a los ratones C57BL/6 y características neuropatológicas distintas, incluidas formaciones de placa únicas.
El análisis bioquímico reveló idénticos fragmentos de PrP resistentes a la proteinasa-K para RMLFFI y RMLCJD.

Conclusiones:

La mutación D178N, independientemente del polimorfismo M129V, confiere propiedades de cepa estables y nuevas a los priones de RML.
Los priones generados in vitro a partir de modelos de ratón D178N no recapitulan completamente el FFI o el CJD178.8.
La prionogénesis espontánea y templada puede implicar diferentes vías mecanicistas.

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