Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult.
Elife
; 62017 04 25.
Article
en En
| MEDLINE
| ID: mdl-28440222
ABSTRACT
The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4). Disruption of PERK signaling delays neurodegeneration without reducing JNK signaling. Furthermore, DLK is both sufficient for PERK activation and necessary for engaging the ISR subsequent to JNK-mediated retrograde injury signaling. These findings identify DLK as a central regulator of not only JNK but also PERK stress signaling in neurons, with both pathways contributing to neurodegeneration.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
EIF-2 Quinasa
/
Quinasas Quinasa Quinasa PAM
/
Degeneración Nerviosa
/
Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Elife
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos