A wounded axon sends out a long-distance distress signal. Huntwork-Rodriguez et al. uncovered a positive feedback loop that might amplify the alarm and help it spread along the axon.
A damaged axon dispatches an alert to the cell body, which fires up genes that—depending on the neuron’s location—trigger healing or cause the axon to degenerate and the cell to die. Key proteins in this response are the c-Jun N-terminal kinases (JNKs), which spur axon deterioration and cell death. Another important protein is the dual leucine zipper-bearing kinase (DLK), which senses axon injury and ramps up JNK activity. Researchers think that the molecular distress call travels along the axon when JNKs hop aboard motor proteins such as dynein.
Huntwork-Rodriguez et al. uncovered the system’s volume knob. They sliced the axons of the optic nerve in mice and found that DLK levels rapidly shot up at the site of the damage. Within three days, the DLK surge had spread to the cell bodies of the neurons. However, the cells weren’t making more DLK; they were destroying less. The researchers discovered that stress causes neurons to reduce their ubiquitylation of DLK, thus sparing the protein from the proteasome.
Phosphorylating DLK at several sites protects it against ubiquitylation. JNKs perform this phosphorylation, setting up a positive feedback loop. The researchers think that cells normally use ubiquitylation to keep DLK levels under tight control. But an injury switches on DLK locally, which in turn flips on JNKs that phosphorylate DLK and prevent ubiquitylation, leading to increased DLK levels and more JNK activation. Without this boost, the response can’t spread toward the cell body.
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Author notes
Text by Mitch Leslie
