Singapore scientists have demonstrated the critical role a special transporter protein plays in regulating brain cells that ensure nerves are protected by coverings called myelin sheaths. The findings, reported by researchers from Duke-NUS Medical School and the National University of Singapore in the Clinical Research Journalcould help reduce the damaging impacts of aging on the brain.
An insulating membrane that coats nerves, myelin sheaths facilitate the rapid and effective conduction of electrical signals throughout the body’s nervous system. When the myelin sheath is damaged, nerves can lose their ability to function and cause neurological disorders. With aging, the myelin sheaths can begin to degenerate naturally, which is why older people lose their physical and mental abilities.
“The loss of myelin sheaths occurs during the normal aging process and in neurological diseases, such as multiple sclerosis and Alzheimer’s disease,” said Dr. Sengottuvel Vetrivel, principal investigator of the Cardiovascular and Metabolic Disorders (CVMD) Program at Duke-NUS and principal investigator of the study. “Developing therapies to improve myelination (the formation of the myelin sheath) in aging and disease is of great importance to alleviate the difficulties caused by decreased myelination.”
To pave the way for the development of such therapies, the researchers sought to understand the role of Mfsd2a, a protein that transports lysophosphatidylcholine (LPC), a lipid containing an omega-3 fatty acid, to the brain as part of the myelination process. . From what is known, genetic defects in the Mfsd2a gene lead to significantly reduced myelination and a birth defect called microcephaly, which causes the baby’s head to be much smaller than it should be.
In preclinical models, the team showed that knocking out Mfsd2a from precursor cells that mature into myelin-producing cells, known as oligodendrocytes, in the brain led to poor myelination after birth. Subsequent research, including single-cell RNA sequencing, demonstrated that the absence of Mfsd2a caused the pool of fatty acid molecules, particularly omega-3 fats, to be reduced in precursor cells, preventing these cells from mature into oligodendrocytes that produce myelin.
“Our study indicates that omega-3 lipids from LPC act as factors within the brain to direct oligodendrocyte development, a process that is critical for myelination of the brain,” explained Professor David Silver, lead study author and deputy director. of the CVMD Program. “This opens up potential avenues for developing omega-3 lipid LPC-based dietary supplements and therapies that could help retain myelin in the aging brain, and possibly to treat patients with neurological disorders stemming from reduced myelination.”
Previously, Professor Silver and his lab discovered Mfsd2a and worked closely with other teams to determine the function of LPC lipids in the brain and other organs. Current research provides further insight into the importance of lipid transport for oligodendrocyte precursor cell development.
“We now aim to perform preclinical studies to determine whether dietary omega-3 LPC can help to re-myelinate damaged axons in the brain,” added Professor Silver. “Our hope is that supplements containing these fats may help maintain, or even improve, brain myelination and cognitive function during aging.”
“Professor Silver has been relentless in investigating the far-reaching role of Msdf2a ever since he discovered this important lipid transport protein, hinting at the many possible ways to treat not only the aging brain but also other organs in which the protein plays a role,” said Professor Patrick Casey, Senior Vice Dean for Research. “It is exciting to see Professor Silver and his team shape our understanding of the roles these specialized lipids play through his many discoveries.”
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