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Diversidad dependiente del contexto y específica de la enfermedad en las interacciones de proteínas dentro de los
Sebastian Markmiller1, Sahar Soltanieh2, Kari L Server1
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92039, USA.
Cell
|January 27, 2018
Resumen
Se analizaron los gránulos de estrés (SG), relacionados con la neurodegeneración, para identificar nuevos componentes. Se encontró un comportamiento anormal de SG en las células de pacientes con ELA, revelando posibles objetivos terapéuticos.
Área de la Ciencia:
- Biología celular
- La neurociencia
- La bioquímica
Sus antecedentes:
- Los gránulos de estrés (SG) son agregados dinámicos de RNP formados durante el estrés celular.
- Los SG están cada vez más implicados en los mecanismos de las enfermedades neurodegenerativas humanas.
Objetivo del estudio:
- Identificar exhaustivamente el proteoma SG humano y la diversidad de composición en todos los tipos de células y contextos neurodegenerativos.
- Investigar el papel de las interacciones de la proteína SG en la formación y dinámica de la SG.
- Explorar las alteraciones de SG en la esclerosis lateral amiotrófica (ELA) e identificar los modificadores in vivo de la neurotoxicidad.
Principales métodos:
- Se utilizó el etiquetado de proximidad de la ascorbato peroxidasa (APEX) junto con la espectrometría de masas.
- Se empleó inmunofluorescencia para la localización de proteínas y la caracterización de SG.
- Dinámica y composición de SG investigadas en células derivadas de pacientes y modelos de Drosophila de ELA/FTD.
Principales resultados:
- Identificó aproximadamente 150 nuevos componentes SG humanos, expandiendo el proteoma SG conocido.
- Reveló una red de interacción de proteínas preexistente que facilita la rápida coalescencia de SG.
- Diversidad de SG dependiente del estrés y el tipo de célula, con SG neuronales que muestran una complejidad única.
- Dinámica, composición y distribución aberrantes de SG observadas en las células de pacientes con ELA.
- Se han identificado modificadores de la neurotoxicidad asociados a la SG en modelos de Drosophila.
Conclusiones:
- Las proteínas SG son fundamentales para comprender la neurodegeneración.
- Los hallazgos proporcionan una base para dirigirse a los SG como una estrategia terapéutica para enfermedades neurodegenerativas.
- La composición y la dinámica de SG son factores críticos en las patologías neurodegenerativas.
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