Nuclear and cytosolic jnk signalling in neurons

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

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LEMUR FAMILY OF PROTEIN KINASES Article Open access 08 January 2024 MOLECULAR MECHANISMS OF CELL DEATH IN NEUROLOGICAL DISEASES Article Open access 07 June 2021 REFERENCES * Kyriakis, J. M.

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  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Turku Centre for Biotechnology, Åbo Akademi University and the University of Turku, Tykistokatu 6, 20520, Turku,

Finland Eleanor T. Coffey Authors * Eleanor T. Coffey View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Eleanor T.

Coffey. ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing financial interests. RELATED LINKS FURTHER INFORMATION HMS LINCS Database POWERPOINT SLIDES POWERPOINT SLIDE

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SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION S1 (TABLE) List of identified JNK substrates. (PDF 134 kb) SUPPLEMENTARY INFORMATION S2 (FIGURE) 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Coffey, E. Nuclear and cytosolic JNK signalling in neurons. _Nat Rev Neurosci_ 15,

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