Descifrando el complejo cerebro del Down

Cada paso que da el zorro, le acerca más a la peleteria

proverbio chino

Su origen se conoce desde hace ya muchos años, pero hasta que no se secuenció el cromosoma 21 no empezaron a acelerarse las investigaciones, que se centraron en conocer la funcionalidad de algunos de los genes implicados. Otro avance ha venido de la mano del desarrollo de modelos murinos con alteraciones similares al síndrome de Down; el siguiente paso es intentar reducir el deterioro cognitivo de los afectados.

En los últimos 30 años se ha avanzado en el conocimiento de cómo se organiza el desarrollo de un organismo y los patrones que generan la morfología. Sin embargo, el proceso cerebral es más complicado, porque una de las características fundamentales del cerebro es su diversidad celular. En otros órganos, el número de células es reducido, por lo que sólo hay que controlar la forma y el tamaño: cuánto proliferan las células y qué forma tienen.

Pero en el cerebro es necesario fijarse en la generación de la diversidad, puesto que existen miles de células diferentes. No sólo es eso: hay que detenerse en la diversidad controlada en el tiempo y en el espacio por la conectividad. Las células tienen que producirse en el número adecuado y en el sitio correcto para conectase con otras y que funcionen bien.

Francisco Tejedor, del Instituto de Neurociencias del Consejo Superior de Investigaciones Científicas y de la Universidad Miguel Hernández, de Alicante, se ha centrado en buscar las localizaciones donde se alteran los procesos específicos de desarrollo del cerebro, “sobre todo en los procesos que regulaban la proliferación de los progenitores”.

A continuación, se fijó en un gen, bautizado como minibrain, “porque los mutantes en este gen producen cerebros más pequeños. Mantienen relativamente la estructura y la conectividad, pero producen menos neuronas”.

Primeros pasos
Su grupo clonó dicho fenotipo y empezó a estudiar su funcionalidad: cómo las proteínas que codifican el gen pueden regular esos procesos.

Una serie de trabajos de los años noventa ha ido intentando acotar qué segmentos dentro del cromosoma 21 son los responsables de la generación de los fenotipos del síndrome de Down. “Son muy variados, puesto que pueden producir alteraciones del crecimiento, cognitivas y físicas, que son las más características”.

También hay que tener en cuenta que el síndrome se produce no sólo por la trisomía del 21 completo, sino por las trisomías parciales, por alteraciones de alguna fracción del 21. “Los genetistas han estado estudiando qué fragmentos son los que producen determinadas alteraciones, y teniendo en cuenta eso, se ha intentado acotar lo que se llama regiones fenotípicas, las que producen ciertos fenotipos”.

El gen minibrain homólogo en humanos está en una de estas regiones críticas. Los fenotipos neuropatológicos son tres. Uno confiere un déficit neuronal: hay determinadas zonas del cerebro que están reducidas y tienen menos número de neuronas; además son importantes para las funciones cognitivas.

El segundo produce una reducción en el tamaño de los árboles dendríticos, es lo que se llama una atrofia dendrítica; y el tercero, una neurodegeneración de tipo Alzheimer muy prematura, que afecta a los individuos a los 35-40 años. “En términos neurológicos es una neurodegeneración prácticamente igual, con aparición de placas, y en términos cognitivos es diferente, puesto que ya tienen un problema cognitivo previo”.

El grupo de Tejedor trabaja en la neurogénesis y ha visto que una función de sobreexpresión del gen minibrain puede causar déficit neuronal y estar implicado en el crecimiento de las dendritas, y que una sobreexpresión del gen podría dar lugar a la atrofia dendrítica.

Este gen parece estar actuando sobre tres funciones que tienen bastante relación con las alteraciones neurológicas del Down. Por esta línea de trabajo del grupo de Tejedor, la Fundación Inocente le ha concedido una ayuda de 29.675 euros dentro de su programa de proyectos de investigación de 2010.

Aunque el origen del síndrome se conoce desde mediados de la década de 1950, los avances en el conocimiento de los mecanismos moleculares que subyacen se están produciendo ahora. El despegue surgió con la secuenciación del cromosoma 21, que permitió identificar los genes y ver su funcionalidad. El segundo aspecto en el que se están consiguiendo grandes avances es, una vez que se han identificado los genes, poder hacer modelos, por lo que han aparecido modelos de ratón con síndrome de Down, que triplican grupos de genes de seres humanos.

Tejedor apunta que ahora el interés se centra en producir herramientas farmacológicas que aminoren la expresión del gen. “Si se pudiera hacer una intervención precoz temprana se podrían mejorar algunos de los defectos cognitivos, pero por ahora toda la investigación en este sentido se está haciendo en modelo de ratón”.

Se están iniciando ensayos clínicos utilizando compuestos que ya están aprobados, pero aún están en las primeras fases. “Lo que está claro es que se tiende a establecer tratamientos individualizados”.

ALIMENTACIÓN

En el desarrollo fetal del cerebro también puede influir la alimentación de la madre, tal y como se ha demostrado en un estudio que ha llevado a cabo el equipo de Peter Nathanielsz, del Centro Médico de la Universidad de Texas, que se ha publicado en Proceedings of the National Academy of Sciences.
La formación de las conexiones entre las células, la división celular y los factores de crecimiento en los fetos de las madres que reducen su dieta durante las primeras fases de la gestación es menor.
El trabajo apunta a que las alteraciones en el desarrollo cerebral fetal asociadas a la pobre dieta de la madre se mantienen durante la edad adulta del niño, ya que pueden provocar problemas en el aprendizaje y en el comportamiento.

Fuente: www.diariomedico.com

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