A new study suggests that how neurons process energy may determine whether they resist damage or begin to break down.
Most cells in the human body can replace themselves when they are damaged, but neurons, the cells that make up the nervous system, generally cannot do this. Once injured, they usually do not generate healthy new copies.
After events such as a stroke, concussion, or neurodegenerative disease, neurons and their axons, the long, threadlike structures that carry electrical signals, are much more likely to deteriorate than to recover. This loss of structure and function is a major driver of long-term neurological decline.
New research from the University of Michigan offers a fresh way of thinking about this process and may point toward strategies to better protect the brain. The study, published in the journal Molecular Metabolism, could also help explain why recovery is possible in rare cases and suggest new directions for treatment development, according to the researchers.
Using a well-established fruit fly model, the team found that a neuron’s ability to withstand damage is closely tied to how it processes sugar.
“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.”
Proteins That Shape Neuronal Fate
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.”
A Delicate Balance Between Protection and Damage
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.”
Implications for Future Therapies
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.”
Reference: “Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection” by Thomas J. Waller, Catherine A. Collins and Monica Dus, 10 June 2025, Molecular Metabolism.
DOI: 10.1016/j.molmet.2025.102187
The research 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.
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1 Comment
Not sure how this applies to humans. But I suppose if you have a pet fruit fly who happens to have nerve damage, you might want him or her to fast. But maybe not. We clearly need more research on this to help neurologically damaged fruit flies. Nice to see human problems have been solved so we can focus on these needy insects.