University of Michigan researchers using fruit flies report that changes in sugar metabolism can influence whether injured neurons and their axons deteriorate or persist. The work, published in *Molecular Metabolism*, describes a context-dependent response involving the proteins DLK and SARM1 that can briefly slow axon degeneration after injury, a finding the team says could inform future strategies for neurodegenerative disease research.
Neurons, the cells that power the nervous system, generally do not replace themselves after damage in the way many other cell types can. After events such as strokes or concussions—and in neurodegenerative diseases—neurons and their axons, the long extensions that carry electrical signals, are often more likely to deteriorate than to repair.
Researchers at the University of Michigan report evidence that a neuron’s fate after injury may be influenced by how it processes sugar. In experiments using Drosophila melanogaster (fruit flies), the team found that disrupting glycolysis by reducing the activity of pyruvate kinase—a key enzyme in sugar metabolism—can undermine axon and synapse integrity in otherwise healthy neurons. But when neurons were already injured, the same metabolic disruption delayed Wallerian degeneration, a form of axon breakdown that follows nerve damage.
The study, led by senior author Monica Dus, an associate professor of molecular, cellular and developmental biology at the University of Michigan, argues that metabolic changes seen in brain injury and disorders such as Alzheimer’s disease may not be merely a byproduct of disease. “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,” Dus said in the university’s account of the work.
Lead author TJ Waller, a postdoctoral research fellow, and colleagues focused on two proteins long studied in axon injury pathways: dual leucine zipper kinase (DLK), which acts as a sensor of neuronal damage, and SARM1 (Sterile Alpha and TIR Motif-containing 1), an enzyme closely linked to axon degeneration. The researchers report that when sugar metabolism was disrupted, DLK signaling and SARM1 activity together were required for progressive axon and synapse degeneration in the fly nervous system.
At the same time, the team found that in the early window after injury—before progressive degeneration took hold—metabolic disruption triggered a protective response that coincided with reduced localization of SARM1 in axons, and this was associated with slower degeneration after nerve injury. The authors describe the result as a context-dependent “rheostat” in which DLK signaling can contribute to short-term protection under some conditions but, when sustained, is linked to progressive neurodegeneration.
That dual role could complicate efforts to target DLK therapeutically, the researchers said, because blocking the pathway outright could also interfere with potentially beneficial stress responses. “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.”
The work was supported by the U.S. National Institutes of Health, the U.S. National Science Foundation, the Rita Allen Foundation and the Klingenstein Fellowship in the Neurosciences, according to the university.
The findings were published as: Thomas J. Waller, Catherine A. Collins and Monica Dus, “Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection,” Molecular Metabolism (2025).
