Can We Protect Brain Cells from Degenerating?

by Mark Terry 

A team of scientists at Temple University, led by Garth Thomas, PhD, recently published research that could lead to a way to block damaged neurons. The research was published in the journal Nature Communications.

Various diseases of the brain, such as Parkinson’s and Alzheimer’s, involve damage to neurons. Dual leucine-zipper kinase (DLK) is an enzyme known to play a role in neuronal damage and loss. DLK signals neurons that they are damaged or sick and triggers a self-destruct sequence. The theory is that blocking this enzyme could slow the progression of these diseases.

Thomas, Associate Professor of Neural Sciences in the Center for Neural Development and Repair at the Lewis Katz School of Medicine at Temple University (Philadelphia), focused on inhibiting DLK as a treatment strategy for neurodegenerative diseases. The research focused on how the damage affects axons, the long, thin spindles that project out of neurons, allowing the transmission of impulses in the brain and spinal cord to other parts of the body. DLK signals axons if they’re sick, telling them to self-destruct.

Earlier attempts to fully block DLK resulted in severe sensory neuropathy. Thomas noted, “This clinical finding suggested that the conventional DLK inhibitor might be disrupting the normal structure and function of axons.”

After confirming that observation, Thomas’s team looked for ways to selectively inhibit DLK. “From some of our previous research, we knew that DLK initiates the self-destruction signals from very specific locations in neurons,” 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.”

They then screened more than 28,000 compounds, identifying two that protected neurons from damage caused by DLK. The compounds also decreased DLK signaling in animal models but didn’t stimulate the axonal disruption seen with traditional DLK inhibition.

Working with medicinal chemists, they developed molecules that were more potent and more specific, as well as stable.

Although early, the researchers believe these compounds are a promising approach to eventually preventing and treating neurodegenerative diseases.

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