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ELAVL4, el empalme y la disfunción glutamatérgica preceden a la pérdida de neuronas en los organoides cerebrales con

Kathryn R Bowles¹, M Catarina Silva², Kristen Whitney³

¹Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA.

|July 27, 2021

Resumen

La investigación de demencia frontotemporal (FTD) utilizando modelos de células madre revela una acumulación temprana de tau y cambios en la vía del glutamato que preceden a la pérdida de neuronas. Un inhibidor de PIKFYVE mostró ser prometedor en el rescate de la toxicidad del glutamato en las neuronas mutantes.

Área de la Ciencia:

La neurociencia
Biología de las células madre
La genética

Sus antecedentes:

La demencia frontotemporal (FTD) está relacionada con mutaciones MAPT, que causan patología tau y muerte neuronal a través de mecanismos poco claros.
La comprensión de los eventos moleculares tempranos es crucial para desarrollar terapias efectivas de FTD.

Objetivo del estudio:

Investigar las alteraciones celulares y moleculares tempranas en organoides cerebrales derivados de células madre pluripotentes inducidas (iPSC) con una mutación MAPT (tau-V337M) que preceden a la neurodegeneración.
Identificar objetivos terapéuticos potenciales para el FTD.

Principales métodos:

Generación y cultivo a largo plazo de organoides cerebrales derivados de iPSC que expresan tau-V337M y controles isogénicos.
Análisis de la expresión génica, el empalme, la agregación de proteínas (tau, P-tau-S396), los gránulos de estrés, la función de autofagia y la vulnerabilidad neuronal a la toxicidad del glutamato en varios momentos (2, 4 y 6 meses).
Experimentos farmacológicos de rescate con un inhibidor de la quinasa PIKFYVE (apilimod).

Principales resultados:

Los organoides mutantes mostraron una regulación temprana de MAPT, las vías de señalización glutamatérgica y ELAVL4, junto con un aumento de los gránulos de estrés a los 2 meses.
Se produjo una acumulación progresiva de cambios de empalme, alteración de la autofagia y acumulación de tau/P-tau-S396 durante 6 meses.
Se observaron pérdidas específicas de neuronas glutamatérgicas y una mayor susceptibilidad a la toxicidad del glutamato en organoides mutantes que fueron rescatados por apilimod.

Conclusiones:

Una secuencia distinta de eventos moleculares, incluida la desregulación de la vía del glutamato, precede a la neurodegeneración en la FTD impulsada por la mutación MAPT.
Las vías de señalización del glutamato representan objetivos terapéuticos prometedores para la DFT.
Apilimod demuestra potencial como agente terapéutico para mitigar la toxicidad del glutamato en FTD.

Palabras clave:

ELAVL4 (en inglés)MAPT (en inglés)La autofagia Demencia frontotemporal Las neuronas glutamatérgicas Organoides y sus derivados el empalme La señalización sináptica Enfermedad de las piernas

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