Signaling through the dual leucine zipper-bearing kinase (DLK) is required for injured neurons to initiate new axonal growth; however, activation of this kinase also leads to neuronal degeneration and death in multiple models of injury and neurodegenerative diseases. This has spurred current consideration of DLK as a candidate therapeutic target, and raises a vital question: in what context is DLK a friend or foe to neurons? Here, we review our current understanding of DLK's function and mechanisms in regulating both regenerative and degenerative responses to axonal damage and stress in the nervous system.

The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.

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