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Mecanismo molecular para la supresión de la toxicidad de la membrana de la sinucleína alfa por una chaperona

Rashik Ahmed¹, Jinfeng Huang², Daniel K Weber³

¹Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton ON L8S 4M1, Canada.

Journal of the American Chemical Society

|May 9, 2020

Resumen

La albúmina sérica humana (HSA) inhibe la toxicidad oligomérica de la alfa sinucleína (αS) en la enfermedad de Parkinson (EP) a través de un mecanismo de varios pasos. HSA se dirige a los oligómeros αS tóxicos, los remodela en formas menos dañinas y bloquea su interacción con las membranas celulares.

Área de la Ciencia:

La neurociencia
La bioquímica
Biología molecular

Sus antecedentes:

Los oligómeros de alfa sinucleína (αS) son fundamentales para la patogénesis de la enfermedad de Parkinson (EP).
La αS extracelular contribuye a la enfermedad de Parkinson a través de una transmisión parecida a la priónica.
La comprensión de la regulación de la αS extracelular es crucial para la terapéutica de la EP.

Objetivo del estudio:

Aclarar el mecanismo por el cual la albúmina sérica humana (HSA) inhibe la toxicidad de los oligómeros αS.
Investigar el papel de la HSA en la red de proteostasis extracelular relevante para la EP.

Principales métodos:

Ensayos bioquímicos para determinar la afinidad y la cinética de la unión HSA-αS.
Análisis estructural de los complejos HSA-αS.
Ensayos basados en células para evaluar la toxicidad del oligómero αS y las interacciones en la membrana.

Principales resultados:

HSA se une a los oligómeros αS con afinidad sub-μM, interrumpiendo la auto-asociación de αS.
El HSA convierte los oligómeros y las fibrillas tóxicas de αS en intermedios quiméricos menos tóxicos.
El HSA inhibe la unión del oligómero αS a las membranas celulares.

Conclusiones:

La HSA actúa como un regulador clave de la toxicidad de la αS extracelular y de la transmisión de célula a célula en la EP.
Los efectos protectores de HSA incluyen la orientación directa de αS, la remodelación estructural y la supresión de la interacción de la membrana.
HSA representa un objetivo o componente terapéutico potencial para mitigar la progresión de la EP.

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