Published May 9, 2017
Researchers at the Hunter James Kelly Research Institute (HJKRI) are highlighting the critical role of a metabolic checkpoint kinase pathway in Schwann cells for the formation of myelin sheaths.
This pathway, centered around the molecule “mammalian target of rapamycin (mTOR),” is known to play a paramount role in the regulation of cell metabolism, growth and cell division, as well as aging.
Nerve cells talk to each other by transmitting electrical signals along communication cables called axons, which are enwrapped by insulating myelin sheaths. The myelin sheaths produced by Schwann cells keep axons energized and healthy, and they facilitate the propagation of electrical signals by a process known as saltatory conduction.
This study, “mTORC1 Promotes Proliferation of Immature Schwann Cells and Myelin Growth of Differentiated Schwann Cells,” has been published as a PNAS Plus article by the Proceedings of the National Academy of Sciences. This type of article is longer and more detailed than the standard papers the journal publishes.
“Myelin sheaths deteriorate in a number of neurodegenerative conditions resulting in axon damage, most prominently in peripheral neuropathies such as diabetic neuropathy that is caused by metabolic tissue imbalances,” says lead and corresponding author Bogdan K. Beirowski, MD, PhD, assistant professor of biochemistry and principal investigator at HJKRI. “The mTOR pathway is clearly dysregulated in these conditions.”
“Diabetic neuropathy affects millions of people in the United States and other developed countries due to our unhealthy living conditions and fast food epidemic,” he adds. “However, the mechanisms as to how mTOR perturbation may affect myelin production are elusive.”
A number of additional diseases are characterized by failed formation of myelin sheaths during development, and researchers are keenly interested in understanding why this happens. Earlier studies suggested that mTOR may be one of the culprits as well.
Together, the implication of mTOR in myelination could provide novel clues toward better understanding how metabolic abnormalities can result in aberrant nerve structure and neurodegeneration.
As part of the study, the scientists showed that genetically manipulated and sick Schwann cells with abnormally high levels of mTOR activity are not able to form myelin sheaths in novel mutant mice.
However, these Schwann cells can be healed and rejuvenated, even after many months of malady in aged animals, by application of a single mTOR inhibitor drug to form new and normal myelin sheaths, Beirowski notes.
The findings from this preclinical study suggest that therapies could be developed to counteract the withering away of myelin sheaths in diseased nerves of patients.
“The study of our novel mouse mutants has uncovered central details in the regulation of myelination by the mTOR pathway in Schwann cells. The involvement of this pathway in myelination has been proposed by other scientists, but our work in Dr. Beirowski’s lab for the first time illustrates the relevance of this fascinating molecule for overall Schwann cell development,” says co-author Keit Men Wong, a doctoral student in the neuroscience program who performed a litany of biochemical and structural analyses for the study.
“This discovery is also important for our understanding of the biological mechanisms underlying nerve regeneration, in which Schwann cells and their myelin sheaths play a pivotal role,” says co-author Elisabetta Babetto, PhD, research assistant professor in the HJKRI.
“However, much more research and hard work is needed to know how exactly this pathway functions in Schwann cells and in conjunction with neurons,” she adds. “Earlier studies have also demonstrated the pathway is involved in neurons itself.”
Beirowski is pursuing several follow-up studies resulting from this collaborative work with Wong and Babetto.
“We are encouraged by our findings and think that our discoveries could be exploited to regenerate myelin sheaths and nerve structure to help patients with neurological disorders,” he says.
The study was initiated in the laboratory of Jeffrey Milbrandt, MD, PhD, of Washington University in St. Louis, who is co-author on the paper.