Credit: Caio Bracey/Macmillan Publishers Limited

Despite recent advances in the understanding of the genetics of chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer disease, the mechanisms underlying these diseases are still poorly understood, which has hampered the development of drug candidates. Now, the group led by Joseph Lewcock has identified dual leucine zipper kinase (DLK) as a common regulator of neuronal degeneration, suggesting that DLK may be a therapeutic target for the treatment of a number of neurodegenerative diseases.

DLK functions as an injury sensor that initiates the c-Jun N-terminal kinase (JNK)-dependent stress response in neurons, and inhibition of the JNK signalling pathway downstream of DLK can slow neuronal degeneration in mice.

First, the authors assessed the extent to which activation of the DLK–JNK pathway correlates with chronic neurodegenerative disease. They found activation of the JNK pathway in the brains of SOD1G93A and TDP-43A315T transgenic mouse models of familial ALS as well as in lumbar spinal cord lysates from patients with sporadic ALS. Aberrant activation of JNK was also found in neurons of two transgenic mouse models of Alzheimer disease (PS2APP and TauP301L) and in post-mortem central nervous system tissues from patients with either early-stage or established Alzheimer disease.

Next, the authors analysed the effect of inhibiting DLK: SOD1G93A mice with normal expression levels of DLK showed a 40% loss of motor neurons, whereas SOD1G93A mice lacking DLK (SOD1G93A;DLKcKO) lost only 13% of motor cells. This increase in neuronal survival after Dlk deletion provided lasting functional benefit, and loss of DLK increased the median lifespan of these mice by 8 days.

In Alzheimer disease models, the authors observed a 30% reduction in the loss of neuronal spines proximal to plaques and enhanced synaptic integrity in PS2APP mice that lacked DLK, which confirmed that Aβ/plaque-associated synaptic loss is partly mediated by DLK signalling. Tamoxifen-induced loss of DLK expression in mice as old as 12 weeks resulted in cognitive improvements.

Finally, the authors tested whether pharmacological inhibition of DLK with two different compounds, GNE-8505 and GNE-351, would also have beneficial effects. Treatment with both inhibitors was well tolerated and reduced the activation of JNK in the spinal cords of SOD1G93A mice compared with vehicle-treated mice. This reduction of DLK–JNK signalling pathway activity was also observed in the brains of PS2APP and TauP301L mice with established disease just 6 hours after receiving one dose. Administration of GNE-3511 in food for 5 weeks delayed neuromuscular junction denervation by ~10% compared with vehicle-treated mice.

DLK inhibitors might hold promise for the treatment of several neurodegenerative diseases, which could be particularly appealing for drug developers.

As DLK expression is specifically enriched in neurons and the DLK–JNK signalling pathway is implicated in multiple disease models, DLK inhibitors might hold promise for the treatment of several neurodegenerative diseases, which could be particularly appealing for drug developers. Indeed, as a result of this study, Genentech has decided to advance a DLK inhibitor (GDC-0134) into a phase I clinical trial in patients with ALS.