An axonal stress response pathway: degenerative and regenerative signaling by DLK

Abstract

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.

Figure 1

DLK regulates multiple responses to axonal damage. DLK signaling becomes activated following axonal injury and regulates multiple cellular responses (in orange): neuronal death [4,7], axonal regeneration [2,3,5,6] and/or protection from degeneration [69], depending upon the context (Table 1). Whether DLK promotes loss of dendrites and synaptic inputs is hypothesized based on discussed data [,,,–31••], but remains to be determined. The distal part of the axon, which becomes removed from the cell body undergoes Wallerian degeneration. This is also influenced by DLK signaling [64,69,103]. In addition, DLK and downstream signaling components crosstalk with other factors that influence axonal degeneration, the NMNAT enzyme and Sarm1 NADylase [18,65,75•,101].

Figure 2

Examples of axonal stress that lead to activation of DLK. Defects in axonal transport [24••], disruption of cytoskeleton within axons [–49], and inhibition of trophic factor signaling [14,41,44•] all result in the activation of DLK signaling. Downstream responses (in orange) include reduced expression levels of presynaptic proteins [24••] and yet unknown signals that impair postsynaptic receptor function and synaptic homeostasis mechanisms [27•]. Over time these responses are expected to promote synaptic decline and loss.

Figure 3

Regulation of DLK. DLK associates with vesicles that are transported in axons (indicated in green) [3,32]. DLK protein is regulated by ubiquitin ligases, including the highly conserved synaptic protein PHR (Pam/Highwire/Rpm-1), which regulates DLK during synaptic development [19,20].