Temple researchers receive $1.25M NIH grant to advance understanding of neurodegenerative diseases

Like wear and tear that causes electrical systems to short circuit, neurons in the human nervous system are susceptible to degenerative processes that disrupt the flow of information. In the human body, faulty transmission between neurons can have serious consequences, leading to conditions known as neuropathies, which cause numbness, pain, tingling, and weakness in affected areas.

Neurons degenerate for a variety of reasons, including genetic factors, conditions such as alcoholism, and exposure to chemicals, toxins, or infectious viruses. In the United States, some 20 million people suffer from neural degeneration that culminates in neuropathy. Many of these individuals are patients with severe diabetes and patients undergoing chemotherapy for cancer.

The fundamental biology underlying neuronal degeneration and neuropathy is not well understood. But now, thanks to a 5-year, $1.25M grant from the National Institutes of Health National Institute of Neurological Disorders and Stroke (NINDS), researchers at the Lewis Katz School of Medicine at Temple University have an opportunity to investigate whether a unique molecular mechanism is common to declining neuronal function observed across multiple neurodegenerative diseases.

In conditions as seemingly diverse as glaucoma, amyotrophic lateral sclerosis (ALS), and diabetes-induced neuropathy, the first part of nerve cells to degenerate are axons, the long, delicate projections that nerve cells extend toward other tissues, including muscle and skin. The discovery of a unifying molecular pathway that drives axon degeneration could open the way to the development of a single drug capable of treating a range of neuropathological conditions.

"The idea that different forms of axon degeneration have a similar mechanism comes from our studies of an axo-degenerative enzyme, Dual Leucine-zipper Kinase (DLK), and how it regulates proteins called axon survival factors," explained Gareth Thomas, PhD, Associate Professor of Neural Sciences and Biomedical Education and Data Science at the Katz School of Medicine, Associate Professor at Shriners Hospitals Pediatric Research Center, and principal investigator on the new grant.

Axon survival factors normally maintain axon health and integrity. In neuropathy, DLK triggers the destruction of the survival factors, leading to axon degeneration. But the mechanism underlying DLK-driven degeneration has been unclear. Dr. Thomas suspects that the key to this destruction process involves the modification of DLK and axon survival factors by a sticky, fatty substance known as palmitate, which attaches DLK and the survival factors to vesicles – tiny, lipid-rich spheres that move rapidly along axons.

With the new NIH funding, Dr. Thomas intends to deepen understanding of the fundamental biology behind this process, known as palmitoylation, and how it controls the destruction of axon survival factors by DLK.

Our hope is that through this work we will be able to identify novel proteins involved in axon survival. Doing so may reveal new therapeutic targets that could guide the development of drugs to ameliorate neurodegenerative conditions."

Dr. Gareth Thomas, Associate Professor

Dr. Thomas will be working closely with collaborators George Smith, PhD, and Gianluca Gallo, PhD, professors in the Department of Neural Sciences at the Katz School of Medicine and Shriners Hospitals Pediatric Research Center, and Linda van Aelst, PhD, Harold and Florence & Ethel McNeill Professor of Cancer Research at Cold Spring Harbor Laboratory. The researchers will carry out their studies in cell and animal models.

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