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  • Review Article
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Nuclear and cytosolic JNK signalling in neurons

Nature Reviews Neuroscience volume 15, pages 285–299 (2014)Cite this article

Subjects

Key Points

  • JUN amino-terminal kinases (JNKs) are dominant regulators of protein phosphorylation in the nervous system.

  • JNKs serve critical functions in developing brain, being required for developmental cell death, neural tube closure, axonal pathfinding, radial migration and dendrite architecture determination.

  • JNKs are sensors of stress, eliciting transcriptional responses in the nucleus and intrinsic death pathway responses in the cytosol, which communicate a strong pro-apoptotic signal.

  • Inhibitors of JNKs or genetic interference approaches prevent the development of Alzheimer's disease hallmarks in preclinical studies.

  • JNKs phosphorylate components of the synaptic machinery, implicating them in synaptic plasticity changes — that is, strengthening or weakening of synapses over time.

  • Recent genetic association studies suggest that JNK pathway gene disruption confers susceptibility to neuropsychiatric disorders — autism, schizophrenia and intellectual disability.

Abstract

It has been over 20 years since JUN amino-terminal kinases (JNKs) were identified as protein kinases that are strongly activated by cellular stress and that have a key role in apoptosis. Examination of Jnk-knockout mice and characterization of JNK behaviour in neuronal cells has further revealed the importance of the JNK family in the nervous system. As well as regulating neuronal death, JNKs govern brain morphogenesis and axodendritic architecture during development, and regulate important neuron-specific functions such as synaptic plasticity and memory formation. This Review examines the evidence that the spatial segregation of JNKs in neurons underlies their distinct functions and that compartment-specific targeting of JNKs may offer promising new therapeutic avenues for the treatment of diseases of the nervous system, such as stroke and neurodegenerative disorders.

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Figure 1: The JNK cascade and JNK isoform expression in the mammalian brain.
Figure 2: JNK function in the cytoplasm.
Figure 3: The nuclear function of JNKs.
Figure 4: JNK function in brain development.
Figure 5: JNK regulates stress responses in the axon.

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Acknowledgements

The author thanks D. Flinkman and P. James for critically reading the manuscript. This research was supported by Åbo Akademi University and the Academy of Finland.

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  1. Turku Centre for Biotechnology, Åbo Akademi University and the University of Turku, Tykistokatu 6, 20520, Turku, Finland

    Eleanor T. Coffey

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FURTHER INFORMATION

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Supplementary information

Supplementary information S1 (table)

List of identified JNK substrates. (PDF 134 kb)

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JNK-targeted therapeutic strategies. (PDF 130 kb)

Glossary

Fluorescence resonance energy transfer sensors

(FRET sensors). Fluorescence resonance energy transfer reporters that detect protein–protein interactions. Here, I refer to a tandem FRET sensor, which transfers light energy of a particular wavelength emitted by a donor fluorophore to an acceptor fluorophore to yield a FRET response that can be harnessed to provide spatiotemporal information on various functional readouts in living cells (for example, kinase activity).

Arborization

A term used to describe the branching or ramification of dendrites.

Excitotoxicity

A type of pathological neuronal death that results from excessive stimulation of glutamate receptors.

AP1

(Activating protein1). AP1 is a transcription factor dimer comprising proteins belonging to JUN, ATF or FOS families.

Exencephaly

A developmental defect in which the brain extrudes outside the skull.

Neurulation

A process during early development of the CNS in which the neural plate is formed. It is followed by neural plate closure and formation of the neural tube.

Commissures

Bundles of nerve fibres that connect the two cerebral hemispheres.

Pial surface

The outer surface of the brain that creates the boundary between the grey matter and the cerebrospinal fluid.

JNK-binding domain

(JBD). JBD is a protein domain found in JUN-amino-terminal kinase (JNK)-interacting protein 1 (JIP1) that competes with JNK for substrate binding and therefore acts as a competitive, non-catalytic site inhibitor.

Radial migration

Newborn glutamatergic neurons of the mammalian neocortex move long distances in synchronized cohorts to produce the six precisely arranged cortical layers. This particular type of neuronal migration is guided by radial glial scaffolds, hence the term radial migration.

Curly-tail phenotypes

This describes the phenotype found in mouse in which the spinal neural tube has failed to close.

Long-term depression

(LTD). A reduction of synaptic strength after application of a long-term, low-intensity stimulus.

Long-term potentiation

(LTP). An increase in synaptic strength after application of a strong tetanus.

Ischaemic preconditioning

This term refers to the protection rendered by exposure to sequential periods of sublethal ischaemia.

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Coffey, E. Nuclear and cytosolic JNK signalling in neurons. Nat Rev Neurosci 15, 285–299 (2014). https://doi.org/10.1038/nrn3729

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