Unlike most cells in the human body, neurons—the functional cells of our nervous system—cannot typically replace themselves with healthy copies after being damaged.
Rather, after an injury from something like a stroke, concussion or neurodegenerative disease, neurons and their axons, fiber-like projections that relay electrical signals, are far more likely to degrade than regenerate.
But new research from the University of Michigan opens new ways to think about neurodegeneration that could help protect patients against that degradation and neurological decline in the future. The study, published in the journal Molecular Metabolism, could even bring us a step closer to understanding the rare cases when brains do heal and open new pathways to developing treatments, the researchers said.
Their findings, made using a well-established fruit fly model, suggest that how resilient neurons are to degradation is connected to the fundamental process of how these cells process sugar. The work was supported by the National Institutes of Health, the U.S. National Science Foundation, the Rita Allen Foundation and the Klingenstein Fellowship in the Neurosciences.
“Metabolism is often changed in brain injury and diseases like Alzheimer’s, but we do not know whether this is a cause or consequence of the disease,” said senior author Monica Dus , U-M associate professor of molecular, cellular, and developmental biology.
“Here we found that dialing down sugar metabolism breaks down neural integrity, but if the neurons are already injured, the same manipulation can preemptively activate a protective program. Instead of breaking down, axons hold on longer.”
Postdoctoral research fellow TJ Waller , the lead scientist in the study, found that two particular proteins appear to be involved in extending the health of axons. One is called dual leucine zipper kinase, or DLK, which senses neuronal damage, and is activated by a disrupted metabolism. The other protein is known as SARM1—short for Sterile Alpha and TIR Motif-containing 1—which has been implicated in axon degeneration and is coupled with the DLK response.
“What surprised us is that the neuroprotective response changes depending on the cell’s internal conditions,” Dus said. “Metabolic signals shape whether neurons hold the line or begin to break down.”
Generally, in cases where neurons and axons don’t degrade, DLK becomes more active and the movement of SARM1 is suppressed. But there are wrinkles. In fact, prolonged DLK activation over time leads to progressive neurodegeneration, the study showed, effectively reversing earlier neuroprotective effects.
DLK, in particular, has emerged as a target for treating and studying neurodegenerative disease. But researchers will need to confront technical challenges to control DLK’s dual harmful and beneficial functionality, Waller said.
“If we want to delay the progression of a disease, we want to inhibit its negative aspect,” Waller said. “We want to make sure that we’re not at all inhibiting the more positive aspect that might actually be helping to slow the disease down naturally.”
Mediating a molecule like DLK’s double functionality presents a compelling puzzle researchers have yet to solve. Uncovering the mechanisms underlying how modulators like DLK switch between these protective and harmful states could hold massive implications for the treatment of neurodegenerative disease and brain injury, directly impacting clinical populations.
Dus and Waller said that understanding this mechanism “provides a new perspective on injury and disease, one that goes beyond simply blocking damage to focusing on what the system is already doing to reinforce it.”
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