by Temple University
Credit: CC0 Public Domain
Neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s involve progressive neuronal loss due to disease-induced damage. An enzyme known as dual leucine-zipper kinase (DLK) plays a key role in this process, telling neurons that are damaged or unhealthy when they should cut their losses and self-destruct. Hence, sparing neurons from DLK is an attractive therapeutic strategy that could slow disease progression.
Past attempts to inhibit DLK’s action in human patients, however, have led to unexpected side effects affecting the nervous system, suggesting that DLK also has beneficial effects on neurons and that blocking it indiscriminately is harmful. Now, in a study published in Nature Communications, a group of scientists led by Gareth Thomas, Ph.D., Associate Professor of Neural Sciences in the Center for Neural Development and Repair at the Lewis Katz School of Medicine at Temple University, describes a more precise way to block DLK in damaged neurons, while preserving its function in healthy neurons.
The research reignites interest in DLK inhibition as a treatment strategy for neurodegenerative disease at a critical time, as cases of Parkinson’s, Alzheimer’s, and other conditions associated with neurodegeneration are poised to double by 2040.
“This study exemplifies the innovative spirit and collaborative strength of our research community at the Katz School of Medicine,” said Amy J. Goldberg, MD, FACS, The Marjorie Joy Katz Dean of the Lewis Katz School of Medicine.
“By uncovering a more precise way to protect neurons, Dr. Thomas and his team are paving the way for treatments that could truly change the trajectory of neurodegenerative diseases.”
In designing their breakthrough approach, Dr. Thomas’s team considered the way damage affects axons—the long, thin projections on neurons that convey impulses within the brain and spinal cord and to other regions of the body. When axons are damaged, DLK sends signals from the site of injury in the axon back to the neuron’s nucleus, which triggers the self-destruction process.
Previous attempts to completely block the enzymatic activity of DLK caused the development of severe sensory neuropathy in patients.
“This clinical finding suggested that the conventional DLK inhibitor might be disrupting the normal structure and function of axons,” explained Dr. Thomas.
Confirming this idea, when his team treated cultured neurons with an existing DLK inhibitor, they indeed saw that axonal structure was rapidly disrupted. This inspired them to seek an alternative approach to more selectively block the enzyme.
“From some of our previous research, we knew that DLK initiates self-destruction signals from very specific locations in neurons,” Dr. Thomas said. “We thought that if we could stop DLK getting to those locations, it wouldn’t be able to initiate the self-destruction process.”
Working with Dr. Wayne Childers at the Moulder Center for Drug Discovery in Temple’s School of Pharmacy and with Dr. Margret Einarson at Fox Chase Cancer Center, Dr. Thomas’s team sought to identify compounds that alter the location of DLK in cells.
“We screened more than 28,000 compounds and eventually hit on two in particular that protect neurons from DLK-driven damage,” Dr. Thomas said.
The two compounds not only protected cultured neurons from degeneration but also reduced DLK signaling in animal models. Very importantly, they did not cause the axonal disruption that they saw with the conventional DLK inhibitor.
“Our findings reveal an exciting, novel way to block DLK-dependent signals,” Dr. Thomas said.
Next steps involve working with medicinal chemists to make the compounds more potent and even more specific to minimize off-target effects.
“The current compounds also need to be made more stable if we want to move forward and develop them as drugs. We hope that moving this class of compounds toward the clinic may yield a valuable therapy for patients in the future,” he added.
Other researchers who contributed to the study include Xiaotian Zhang, Heykyeong Jeong, Jingwen Niu, Sabrina M. Holland, and Brittany N. Rotanz, Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University; and John Gordon, Moulder Center for Drug Discovery, School of Pharmacy, Temple University.
More information: Inhibiting acute, axonal DLK palmitoylation is neuroprotective and avoids deleterious effects of cell-wide DLK inhibition, Nature Communications (2025). DOI: 10.1038/s41467-025-58036-6
Journal information:Nature Communications
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