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Regulación de la α-sinucleína por las chaperonas en las células de mamíferos

Björn M Burmann^1,2,3, Juan A Gerez⁴, Irena Matečko-Burmann^5,6,7

¹Biozentrum, University of Basel, Basel, Switzerland. bjorn.marcus.burmann@gu.se.

|December 6, 2019

Resumen

Las chaperonas moleculares previenen la agregación de alfa-sinucleína en la enfermedad de Parkinson. La inhibición de esta interacción causa agregación tóxica y daño mitocondrial, ofreciendo nuevos objetivos terapéuticos.

Área de la Ciencia:

La neurociencia
Biología molecular
La bioquímica

Sus antecedentes:

La enfermedad de Parkinson involucra cuerpos de Lewy formados por alfa-sinucleína agregada.
La agregación de alfa-sinucleína está influenciada por modificaciones post-traduccionales y chaperonas moleculares, pero los mecanismos no están claros.

Objetivo del estudio:

Caracterizar sistemáticamente las interacciones de las chaperonas con la alfa-sinucleína a nivel atómico.
Para aclarar el papel de estas interacciones en la regulación de la agregación de alfa-sinucleína en las células.

Principales métodos:

Espectroscopia de RMN in vitro y en las células.
Caracterización sistemática de las interacciones chaperona-alfa-sinucleína.
Inhibición de las interacciones de la chaperona y análisis de la localización y agregación de la alfa-sinucleína.

Principales resultados:

Seis chaperones divergentes reconocen un motivo común en la alfa-sinucleína, inhibiendo su agregación.
Esta interacción se conserva en las células de mamíferos vivos.
La inhibición de la interacción de la chaperona conduce a la agregación de la alfa-sinucleína y a la relocalización mitocondrial.
La fosforilación en Tyr39 deteriora la interacción de la chaperona, lo que explica el papel de la cinasa de Abelson.

Conclusiones:

Se establece un mecanismo regulador maestro para la agregación de alfa-sinucleína por chaperonas moleculares.
Esto pone de relieve nuevas estrategias terapéuticas para la enfermedad de Parkinson dirigidas a las interacciones de acompañamiento.

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