La acumulación de esteroles insaturados 8,9 impulsa la formación de oligodendrocitos y la remielinización

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Zita Hubler¹, Dharmaraja Allimuthu¹, Ilya Bederman²

¹Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

|July 27, 2018

Resumen

Las moléculas pequeñas que promueven la regeneración de la mielina en el sistema nervioso central (SNC) se dirigen a las enzimas de síntesis del colesterol. La acumulación de esteroles específicos impulsa la formación de oligodendrocitos, lo que revela un mecanismo unificador para las terapias de remielinización.

Área de la Ciencia:

La neurociencia
La bioquímica
Biología celular

Sus antecedentes:

La regeneración de mielina en el sistema nervioso central (SNC) es crucial para el tratamiento de trastornos neurológicos como la esclerosis múltiple.
Las células progenitoras de oligodendrocitos (OPC) son células madre clave responsables de la generación de nuevos oligodendrocitos mielinantes.
Las moléculas pequeñas existentes tienen como objetivo estimular la diferenciación de OPC y mejorar la remielinización in vivo.

Objetivo del estudio:

Elucidar el mecanismo de acción de las pequeñas moléculas que promueven la formación de oligodendrocitos.
Identificar los objetivos moleculares específicos y las vías involucradas en la actividad de las pequeñas moléculas pro-mielinizantes.
Definir un mecanismo unificador para mejorar la remielinización y orientar el desarrollo terapéutico futuro.

Principales métodos:

Cribado químico de alto rendimiento para identificar moléculas pequeñas pro-mielinizantes.
Pruebas de inhibición enzimática para determinar objetivos moleculares directos.
Análisis de esteroles para identificar los sustratos acumulados.
Estudios in vitro con células progenitoras de oligodendrocitos purificados (OPC).

Principales resultados:

Las pequeñas moléculas pro-mielinizantes inhiben las enzimas específicas de la biosíntesis del colesterol: CYP51, TM7SF2 o EBP.
La inhibición conduce a la acumulación de esteroles 8,9 insaturados, que son esenciales para promover la diferenciación de los OPC.
El suministro de esteroles purificados de 8,9 insaturados impulsa efectivamente la formación de oligodendrocitos.
Los esteroles que carecen de la característica de insaturación 8,9 no promueven la formación de OPC.

Conclusiones:

La mayoría de los potenciadores de moléculas pequeñas conocidos de la formación de oligodendrocitos comparten un mecanismo de acción común basado en esteroles.
Dirigirse a enzimas específicas en la vía de la biosíntesis del colesterol ofrece una nueva estrategia terapéutica para la remielinización.
Este descubrimiento pone de relieve los objetivos clave para desarrollar medicamentos remielinizantes más efectivos para los trastornos del SNC.

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