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Los inhibidores de la histona desacetilasa detienen la neurodegeneración dependiente de la poliglutamina en

J S Steffan¹, L Bodai, J Pallos

¹Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, California 92697, USA.

|October 19, 2001

Resumen

Las proteínas de poliglutamina expandidas causan enfermedades neurodegenerativas. La inhibición de la histona desacetilasa (HDAC) puede revertir el daño neuronal y reducir la letalidad en modelos de enfermedades, ofreciendo una terapia potencial.

Área de la Ciencia:

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

Sus antecedentes:

Las repeticiones expandidas de poliglutamina en proteínas como la huntingtina (Htt) son fundamentales para la enfermedad de Huntington y otros trastornos neurodegenerativos.
La desregulación transcripcional y la disfunción de los coactivadores transcripcionales son mecanismos patológicos clave en estas enfermedades.

Objetivo del estudio:

Para investigar la interacción entre la proteína Htt exon 1 (Httex1p) que contiene poliglutamina y los coactivadores de la transcripción.
Determinar el efecto de Httex1p en la acetilación de histonas y el potencial terapéutico de los inhibidores de la histona desacetilasa (HDAC) en enfermedades por poliglutamina.

Principales métodos:

Ensayos de unión in vitro para evaluar la interacción de Httex1p con la proteína de unión CREB (CBP) y el factor asociado p300/CBP (P/CAF).
Los ensayos de actividad enzimática miden la inhibición de la actividad de la acetiltransferasa por Httex1p.
Experimentos de cultivo celular para evaluar el impacto de Httex1p en los niveles de acetilación de histonas y el efecto de los inhibidores de HDAC.
Estudios in vivo utilizando modelos de Drosophila para evaluar la eficacia de los inhibidores de HDAC en la mitigación de la neurodegeneración y la letalidad.

Principales resultados:

Httex1p se une directamente a los dominios de la acetiltransferasa de CBP y P/CAF.
Httex1p inhibe la actividad de la acetiltransferasa de p300, P/CAF y CBP en sistemas libres de células.
La expresión de Httex1p en células cultivadas conduce a niveles reducidos de histonas H3 y H4 acetiladas, que es reversible por los inhibidores de HDAC.
In vivo, los inhibidores de HDAC detienen efectivamente la degeneración neuronal progresiva y disminuyen la letalidad en modelos de Drosophila de enfermedad por poliglutamina.

Conclusiones:

El dominio Htt que contiene poliglutamina interfiere directamente con la función de los coactivadores clave de la transcripción.
La inhibición de la histona deacetilasa (HDAC) representa una estrategia terapéutica prometedora para ralentizar o prevenir la neurodegeneración en la enfermedad de Huntington y otros trastornos de repetición de poliglutamina, incluso después del inicio de los síntomas.

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