Glucose acts as a metabolic signal for myelin development

Researchers at the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) have uncovered a surprising link between low brain sugar levels and the development of myelin - the protective coating that allows nerve cells to communicate rapidly and efficiently. The study, set for publication in Nature Neuroscience, reveals that the glucose-sensing ability of stem-like cells during early development helps them determine whether they should multiply and remain undifferentiated or mature into myelin-forming cells, thereby shaping brain development.

Myelin is the membrane of specialized cells called oligodendrocytes, which arise from progenitor cells, called oligodendrocyte progenitor cells (OPCs). Myelination begins before birth and continues into adulthood, supporting critical milestones such as sitting, crawling, walking, and talking.

Scientists have long puzzled over why myelin forms at different times in different brain regions. The CUNY ASRC team discovered that local changes in glucose (the brain's main energy source) act as a signal that directs behavior during development.

Using advanced technology at the CUNY ASRC MALDI Imaging Core Facility (co-directed by professors Rinat Abzalimov and Ye He), the researchers mapped glucose levels across developing mouse brains. They found that glucose levels vary by region and over time. Areas with higher glucose levels had more actively dividing OPCs while areas with lower glucose levels contained cells beginning to mature into myelin-producing oligodendrocytes.

"Our findings show that glucose is not just fuel for the brain, it's also a signal for the cells to divide," said lead author Sami Sauma, a postdoctoral researcher with the CUNY ASRC Neuroscience Initiative who received his Ph.D. from Graduate Center. "We found that when glucose levels are high in a particular brain region, progenitors use it to drive proliferation. As glucose levels shift, the same cells switch gears and begin maturing. It's a beautifully coordinated metabolic system that helps shape brain development."

At the center of this process is an enzyme called ATP-citrate lyase (ACLY). ACLY converts glucose-derived molecules into acetyl-CoA in the cell nucleus, enabling chemical changes to DNA-associated proteins that activate genes required for cell proliferation.

When the researchers genetically deleted ACLY in OPCs, those cells could no longer multiply effectively. As a result, mice showed a temporary reduction in myelin due to a smaller pool of progenitor cells. Remarkably, however, the cells were still able to mature into myelin-producing oligodendrocytes by switching to alternative metabolic sources.

The team discovered that while progenitor cells depend on glucose-derived acetyl-CoA to multiply, mature oligodendrocytes rely on acetyl-CoA generated outside the nucleus from other fuels, such as ketone bodies, to produce myelin.

In fact, when transgenic mice lacking the ACLY enzyme in OPCs were placed on a ketogenic diet, which increases ketone levels in the blood, their myelin deficits improved.

Patrizia Casaccia, founding director of the CUNY ASRC Neuroscience Initiative and Einstein Professor of Biology at the CUNY Graduate CenterThis study reveals that the same cell lineage interprets different metabolic signals at distinct stages of development. By understanding how glucose and alternative energy sources regulate proliferation and myelin formation, we are uncovering new metabolic strategies that could be harnessed to protect myelin in the developing brain and even promote repair in disease states."

The developmental window studied in mouse models corresponds to approximately 32 to 40 weeks of human gestation, which is a critical period when premature birth can result in white matter injury. The findings suggest that metabolic support during this vulnerable stage could help protect progenitor cells responsible for building myelin.

The implications may also extend to neurological disorders characterized by myelin loss in children and adults, including multiple sclerosis. By targeting the metabolic pathways that regulate progenitor cell proliferation and oligodendrocyte maturation, researchers may be able to design new therapies to enhance myelin repair.

As scientists continue to uncover how metabolism shapes brain development, this research highlights a powerful and potentially modifiable influence on how the brain builds its essential wiring.

The study was supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

Source:

Advanced Science Research Center, GC/CUNY

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