La autofagia, posible arma contra proteínas mal plegadas

Las ciencias aplicadas no existen, sólo las aplicaciones de la ciencia

Louis Pasteur

Comprender la biología más básica de los mecanismos de control de calidad y degradación celular es el punto de partida para mejorar el abordaje de diversas patologías. Sobre este aspecto trabaja Ron Kopito, catedrático de Biología en la Universidad de Stanford, en California, Estados Unidos, que ha visitado la Fundación BBVA, en Madrid. Antes de su charla ha explicado a Diario Médico algunas claves de sus estudios.

Una de las grandes preguntas reside en saber cómo la célula discierne si una proteína se pliega correctamente o no, desencadenando en este último caso toxicidad y desarrollo patológico: “Si el plegamiento es correcto se produce una estructura muy específica, por lo que en principio se podría saber cuándo es la correcta. Pero hay más de 50.000 proteínas distintas en la célula y difícil disponer de un sensor para cada una de ellas”. Por el momento, la mayoría de rasgos característicos de un buen plegamiento aún son desconocidos.

Cuerpos de inclusión
Estudiar el proteosoma es una vía adecuada. Es “el mayor basurero de la célula, que se encarga de todas las proteínas que no se han plegado correctamente”. Kopito persigue descubrir si realmente se encuentra defectuoso en enfermedades neurodegenerativas.

Los patólogos han hallado que la ubiquitina, “punto de partida para llegar hasta el proteosoma, estaría implicada. Creemos que algo falla y que el proteosoma no puede depurar toda la información que le llega, por lo que ésta se acumula y forma los cuerpos de inclusión, depósitos de proteínas con errores de plegamiento”.

Su laboratorio trabaja en patologías neurodegenerativas y enfermedades genéticas recesivas como la fibrosis quística, ambas causadas por problemas de control de calidad celular. Se trata de las dos caras de una moneda, de problemas opuestos; mientras en neurodegeneración hay una sobreacumulación de proteínas potencialmente funcionales, en fibrosis quística hay una escasez debido a la destrucción de proteínas que también tienen capacidad para funcionar correctamente.

Así, “tan malo es disponer de muchas como de pocas proteínas. Si funcionan mal, hay un problema, pero también si hay un exceso de eficiencia, porque éste es el punto de partida de diversas enfermedades metabólicas”.

Conocer mejor los priones
La autofagia es otro proceso vital. El equipo de Kopito cree que destruye proteínas que el proteosoma no es capaz de eliminar: “Hemos hallado evidencias de que el proteosoma está especialmente activo en la mayoría de enfermedades neurodegenerativas. Sugerimos, aunque no podemos afirmarlo, que este proceso trata de ayudar a la célula a deshacerse de un exceso de proteínas”. Si fuera cierto, la autofagia podría usarse contra los cuerpos de inclusión, aunque por el momento “sólo comprendemos una pequeña fracción de estos mecanismos”.

El trabajo de Kopito podría desentrañar la labor de los priones, proteínas con plegamientos anómalos ligadas a la neurodegeneración cuya evolución aún es un misterio: “Estos elementos no genéticos aprovechan a su gusto el sistema de control de calidad celular para replicarse, según hemos visto en organismos menores”. Las chaperonas permiten replicar el agente priónico, otra proteína que finalmente deriva en “el que parece ser el tipo de agregado que aparece en las patologías neurodegenerativas”. 

Fuente: www.diariomedico.com

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