JNK Pathway in CNS Pathologies

Abstract

The c-Jun N-terminal kinase (JNK) signalling pathway is a conserved response to a wide range of internal and external cellular stress signals. Beside the stress response, the JNK pathway is involved in a series of vital regulatory mechanisms during development and adulthood that are critical to maintain tissue homeostasis. These mechanisms include the regulation of apoptosis, growth, proliferation, differentiation, migration and invasion. The JNK pathway has a diverse functionality and cell-tissue specificity, and has emerged as a key player in regeneration, tumorigenesis and other pathologies. The JNK pathway is highly active in the central nervous system (CNS), and plays a central role when cells need to cope with pathophysiological insults during development and adulthood. Here, we review the implications of the JNK pathway in pathologies of the CNS. More specifically, we discuss some newly identified examples and mechanisms of JNK-driven tumor progression in glioblastoma, regeneration/repair after an injury, neurodegeneration and neuronal cell death. All these new discoveries support the central role of JNK in CNS pathologies and reinforce the idea of JNK as potential target to reduce their detrimental effects.

Keywords: CNS injuries; MAP kinase; cell signalling; glioblastoma; neurodegenerative disorders.

Figure 1

The JNK pathway is conserved between mammals and flies. Upon internal and external stress stimuli, ligands (ex. TNF/Egr) activate transmembrane receptors (ex. TNFαR/ Grnd) and initiate a cellular response based on a MAPK cascade phosphorylation. In mammals, different ligands can trigger the signal path; while in Drosophila, Eiger (Egr) is the TNF ligand that predominantly initiates the stress response via TNF receptors (Grindewal, Grnd; or Wengen, Wng). In mammals, there is MAPK path gene redundancy that is shown in this diagram compared with flies. MAPKs are encoded by multiple genes in mammals, whereas in Drosophila, one single gene is described for each enzyme. The cellular response converges in JNK/Bsk phosphorylation, which triggers the expression of transcription factors as Jun/Jra and Fos/Jay, known as an AP-1/dAP-1 complex. Finally, AP1/dAP-1 modulates the transcriptional program of genes involved in a variety of biological activities. This pathway can be activated at other steps indicated with dotted lines in the diagram.

Figure 2

JNK pathway in CNS pathologies. (A) JNK integrates a positive loop promoting tumour growth and neurodegeneration. GB cells extend a TM network wrapping the surrounding neurons, promoting glia–neuron signalling communication. TMs filaments deplete neuronal Wg/WNT and Egr/TNF and relocalize Frizzled 1 and Grnd to activate the JNK pathway in tumor cells. JNK activation leads to MMP transcription, required for tumor infiltration into the healthy tissue, which expands the TM network, thereby describing a positive feedback loop. As a result, neurons degenerate. Neurodegeneration is also reinforced by the JNK-Impl2-InR signal in neurons, which alters mitochondrial metabolism and facilitates synapse loss and neuronal death. (B) Neuronal and glial JNK mediates different pathways upon CNS injury. JNK activation in injured axons promotes axon degeneration through the activation of downstream molecules such as ATF3/Hsp27 and KLF9, which in turn inhibit axonal growth or members of the Bcl-2 family to trigger apoptosis. JNK activation in injured axons also promotes microtubule stability and axonal growth through Wnd/MAP3K/DLK-1 phosphorylation. JNK activation in glial cells upon injury is triggered by Draper, and it is required for further Draper activation, as well as for cell-debris removal. JNK activates MMP-1, necessary for glial infiltration for cell-debris clearance. This phagocytic response is necessary for axonal regeneration.