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Muerte axonal patológica a través de una cascada de MAPK que desencadena un déficit energético local
Jing Yang1, Zhuhao Wu1, Nicolas Renier1
1Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
Cell
|January 17, 2015
Resumen
La degeneración axonal, un sello distintivo de las enfermedades neurodegenerativas, implica una vía Sarm1-MAPK recientemente identificada que agota la energía axonal. Las proteínas protectoras como cytoNmnat1/Wld(s) y la señalización AKT regulan esta vía.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- La muerte axonal deteriora la conectividad del circuito neuronal y es fundamental para los trastornos neurodegenerativos.
- Los mecanismos de degeneración de axones patológicos, independientes de la muerte celular programada, son en gran parte desconocidos.
Objetivo del estudio:
- Para investigar las familias de proteína quinasa activada por mitógeno (MAPK) en la lesión axonal.
- Para delinear la cascada molecular involucrada en las respuestas tempranas de degeneración axonal.
Principales métodos:
- Utilizó un modelo de lesión axonal traumática.
- Familias MAPK sistemáticamente investigadas.
- Se examinaron las funciones de la señalización Sarm1, cytoNmnat1/Wld(s), MKK4, AKT y JNK.
Principales resultados:
- Identificó una cascada de MAPK dependiente de Sarm1 como una respuesta temprana a una lesión axonal.
- Se demostró que esta vía interrumpe la homeostasis de la energía axonal, causando el agotamiento del ATP.
- Se encontró que cytoNmnat1/Wld(s) inhibe la cascada MAPK, mientras que la señalización AKT antagoniza MKK4 para modular la señalización JNK.
Conclusiones:
- Se reveló un mecanismo regulador que integra la señalización Sarm1-MAPK, cytoNmnat1/Wld(s) y AKT/JNK en la degeneración axonal patológica.
- Esta vía representa un determinante crítico de la integridad axonal después de una lesión.
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