Philly Leader

Researchers at the Lewis Katz School of Medicine at Temple University have identified a new method to protect neurons from degeneration. Neurodegenerative diseases like Parkinson's and Alzheimer's are marked by the progressive loss of neurons, often influenced by an enzyme called dual leucine-zipper kinase (DLK). While past efforts to block DLK resulted in adverse effects, new research offers a targeted approach that might avoid those pitfalls.

The study, led by Dr. Gareth Thomas from the Center for Neural Development and Repair at the Lewis Katz School of Medicine, was published online in the journal Nature Communications on April 3. The findings suggest a method to inhibit DLK in damaged neurons while preserving its function in healthy ones.

As cases of neurodegenerative diseases are predicted to double by 2040, the research is timely. “This study exemplifies the innovative spirit and collaborative strength of our research community at the Katz School of Medicine,” stated Amy J. Goldberg, MD, FACS, The Marjorie Joy Katz Dean. “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.”

Dr. Thomas and his team focused on the role of DLK related to the axons in neurons. Axons, responsible for sending impulses within the central nervous system, are the site where DLK initiates damage signals when injured. Previous complete inhibition of DLK resulted in severe sensory neuropathy, leading to the disruption of axonal structure. “This clinical finding suggested that the conventional DLK inhibitor might be disrupting the normal structure and function of axons,” Dr. Thomas explained.

To address this, the research team collaborated with Dr. Wayne Childers at the Moulder Center for Drug Discovery and Dr. Margret Einarson at Fox Chase Cancer Center. They screened over 28,000 compounds and found two that protect neurons without the negative effects previously seen with conventional inhibitors. “From some of our previous research, we knew that DLK initiates the self-destruction signals from very specific locations in neurons,” Dr. Thomas said. “We thought that if we could stop DLK from getting to those locations, it wouldn’t be able to initiate the self-destruction process.”

The next steps involve enhancing the potency and specificity of these compounds, aiming to minimize off-target effects and improve stability for clinical development. “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,” Dr. Thomas noted.

Contributors to the research include Xiaotian Zhang, Heykyeong Jeong, Jingwen Niu, Sabrina M. Holland, and Brittany N. Rotanz from the Center for Neural Development and Repair, alongside John Gordon from the Moulder Center for Drug Discovery. Funding for the research was provided by the National Institutes of Health, Shriners Children’s, and the BrightFocus Foundation.