Biochemist IDs Pathway Central to Stability of Nerve Axons

The research by first author Bogdan K. Beirowski, MD, PhD, assistant professor of biochemistry, has been published in Nature Neuroscience and featured as a research highlight in Nature Reviews Neuroscience.

Glia, including Schwann cells, enwrap axons and are believed to provide metabolic support for these long nerve cell projections.

“We found that LKB1 — a key regulatory pathway of metabolic activity in Schwann cells — is central to axon stability in nerves,” says Beirowski, also principal investigator at the Hunter James Kelly Research Institute.

“Disruption of LKB1 signaling and the resulting perturbations in Schwann cell metabolism might contribute to axon degeneration in metabolic diseases such as diabetic neuropathy — a devastating condition observed in about half of all long-term diabetes patients — and perhaps in other forms of neurodegeneration,” Beirowski concludes.

“Because of their energetic demand and incredible length — up to 1 meter in humans — axons are very vulnerable and at continuous risk of damage,” Beirowski notes. “In neuropathies, such as diabetic neuropathy, axons in nerves degenerate when maintenance functions fail.”

“Our study provides a molecular basis, with emphasis on metabolic pathways, for new therapeutic avenues for neuropathies centered on glia.”

In experiments with mice, the research team deactivated LKB1 only in Schwann cells, leading to metabolic misbalances in these glia.

“Surprisingly, this resulted in striking axon degeneration as the mutant mice aged, but did not cause overt Schwann cell abnormalities,” says Beirowski.

“The patterns of axon degeneration remarkably resembled those occurring in diabetic neuropathy.”

The researchers also manipulated the classical targets of the LKB1 pathway, such as AMP-activated kinase — a master metabolic regulating enzyme. Unexpectedly, they found these did not account for the axon degeneration.

In addition, the scientists applied high-throughput metabolomics technology to perform a global characterization of metabolite levels in the nerves of mice with glial LKB1 deletion.

“This showed abnormal concentrations of several metabolites, providing significant clues for the most important metabolic pathways in Schwann cells that help to support axons,” says Beirowski.

Their study, “Metabolic Regulator LKB1 is Crucial for Schwann Cell–Mediated Axon Maintenance,” was reviewed in Nature Neuroscience by Iva D. Tzvetanova and Klaus-Armin Nave of the Max Planck Institute for Experimental Medicine in Göttingen, Germany.

Citing several questions yet to be answered, the reviewers note: “For now, the simple message is that metabolic interactions also exist between Schwann cells and their associated axons, and yes, they are complex.”

Beirowski, who joined UB in the fall, collaborated with former colleagues at Washington University in St. Louis including experts in genetics, developmental biology, pain, neurological disorders, bioorganic chemistry and molecular pharmacology.