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Receptores de importación nuclear Transiciones de fase aberrantes inversas de las proteínas de unión al ARN con

Lin Guo¹, Hong Joo Kim², Hejia Wang¹

¹Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

|April 21, 2018

Resumen

Los receptores de importación nuclear (NIR) previenen y revierten la agregación de proteínas patológicas en enfermedades neurodegenerativas. Karyopherin-β2 se dirige específicamente a las proteínas de unión al ARN (RBPs) con dominios similares a los priones, restaurando la función celular y mitigando la progresión de la enfermedad.

Área de la Ciencia:

Neurobiología
Biología molecular
La bioquímica

Sus antecedentes:

Las proteínas de unión al ARN (RBPs) con dominios similares a priones (PrLDs) pueden formar agregados patológicos implicados en enfermedades neurodegenerativas.
La localización errónea y la agregación de RBP nucleares como TDP-43 y FUS son las características de estos trastornos.
Las mutaciones en las PrLD pueden acelerar la fibrilación RBP y la aparición de la enfermedad.

Objetivo del estudio:

Investigar el papel de los receptores de importación nuclear (NIR) en el acompañamiento y la desagregación de RBPs con PrLD.
Determinar si las NIR pueden revertir las transiciones de fase patológica y la formación de fibrillas de las RBP asociadas a la enfermedad.
Evaluar el potencial terapéutico de las NIR in vivo para los trastornos neurodegenerativos.

Principales métodos:

Ensayos in vitro para evaluar los efectos de la Karyopherin-β2 y de la Importin-α/Karyopherin-β1 en la fibrilización de la RBP y en la formación de hidrogel.
Análisis de la separación y desagregación de las fases de la RBP.
Estudios in vivo en organismos modelo para evaluar el impacto de Karyopherin-β2 en la localización, función y neurodegeneración de la RBP.

Principales resultados:

Karyopherin-β2 inhibe y revierte la fibrilación de FUS, TAF15, EWSR1, hnRNPA1 y hnRNPA2 mediante la activación de sus señales de localización nuclear (NLS).
Importin-α/Karyopherin-β1 previene y revierte la fibrilación TDP-43.
Karyopherin-β2 disuelve líquidos y hidrogeles separados por fases aberrantes formados por FUS y hnRNPA1.
In vivo, la Karyopherin-β2 previene la agregación de la RBP, restaura la localización y la función nuclear y rescata la neurodegeneración.

Conclusiones:

Los receptores de importación nuclear, particularmente Karyopherin-β2, actúan como potentes desagregas para las RBP asociadas a la enfermedad.
Los NIR restauran terapéuticamente la homeostasis de la RBP al prevenir las transiciones de fase aberrantes y la formación de fibrillas.
La orientación de las NIR ofrece una estrategia terapéutica prometedora para mitigar la neurodegeneración.

Palabras clave:

La ELA Dispositivos para el trabajo de la mano FUS y sus derivados Caryoferina-β2 y sus derivados Receptor de importancia nuclear TDP-43 (en inglés)desagregación En el caso de las personas físicas:neurodegeneración transición de fase

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