omega-3 脂肪酸脂化在非植物性衰老中的主要作用

具有有髓鞘轴突（以绿色显示）的开发中的临床前模型的大脑。 来自新加坡的科学家发现了转运蛋白 Mfsd2a 在调节维持髓鞘（包裹神经的绝缘膜）的脑细胞中的关键作用。 这些结果发表在 临床研究杂志它可能有助于减少衰老对大脑的影响。 Mfsd2a 将溶血磷脂酰胆碱 (LPC)（一种含有 omega-3 脂肪酸的脂质）转运至大脑用于骨髓发生。 图片来源：Vetrivel Sengotuvil 博士

研究人员发现，Mfsd2a 转运蛋白对于调节维持保护神经的髓鞘的脑细胞至关重要。 这一发现可能有助于减少衰老对大脑的影响，并有助于治疗由骨髓生成减少引起的神经系统疾病。

来自新加坡的科学家已经证明了一种特殊的转运蛋白在调节脑细胞方面发挥的关键作用，这种脑细胞确保神经受到称为髓鞘的覆盖物的保护。 该研究结果由杜克-新加坡国立大学医学院和新加坡国立大学的研究人员于 2018 年发表 临床研究杂志它可以帮助减少衰老对大脑的有害影响。

髓鞘是一种围绕神经的绝缘膜，有助于电信号在整个身体神经系统中快速有效地传导。 当髓鞘受损时，神经可能会失去功能并导致神经系统疾病。 随着年龄的增长，髓鞘可能会自然开始退化，这就是为什么老年人会丧失身心能力。

髓鞘的丢失发生在正常的衰老过程和神经退行性疾病中，例如多发性硬化症和[{” attribute=””>Alzheimer’s disease,” said Dr. Sengottuvel Vetrivel, Senior Research Fellow with Duke-NUS’ Cardiovascular & Metabolic Disorders (CVMD) Program and lead investigator of the study. “Developing therapies to improve myelination—the formation of the myelin sheath—in aging and disease is of great importance to ease any difficulties caused by declining myelination.”

To pave the way for developing such therapies, the researchers sought to understand the role of Mfsd2a, a protein that transports lysophosphatidylcholine (LPC)—a lipid that contains an omega-3 fatty acid—into the brain as part of the myelination process. From what is known, genetic defects in the Mfsd2a gene leads to significantly reduced myelination and a birth defect called microcephaly, which causes the baby’s head to be much smaller than it should be.

Dr. Sengottuvel Vetrivel (left) and Prof David Silver (right). Credit: Duke-NUS Medical School

In preclinical models, the team showed that removing Mfsd2a from precursor cells that mature into myelin-producing cells—known as oligodendrocytes—in the brain led to deficient myelination after birth. Further investigations, including single-cell RNA sequencing, demonstrated that Mfsd2a’s absence caused the pool of fatty acid molecules—particularly omega-3 fats—to be reduced in the precursor cells, preventing these cells from maturing into oligodendrocytes that produce myelin.

“Our study indicates that LPC omega-3 lipids act as factors within the brain to direct oligodendrocyte development, a process that is critical for brain myelination,” explained Professor David Silver, the senior author of the study and Deputy Director of the CVMD Program. “This opens up potential avenues to develop therapies and dietary supplements based on LPC omega-3 lipids that might help retain myelin in the aging brain—and possibly to treat patients with neurological disorders stemming from reduced myelination.”

Previously, Prof 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. The current research provides further insights into the importance of lipid transport for oligodendrocyte precursor cell development.

“We’re now aiming to conduct preclinical studies to determine if dietary LPC omega-3 can help to re-myelinate damaged axons in the brain,” added Prof Silver. “Our hope is that supplements containing these fats can help to maintain—or even improve—brain myelination and cognitive function during aging.”

“Prof Silver has been relentless in investigating the far-reaching role of Msdf2a ever since he discovered this important lipid transport protein, alluding to the many possible ways of treating 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’s exciting to watch Prof Silver and his team shape our understanding of the roles that these specialized lipids play through their many discoveries.”

Reference: “Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination” by Vetrivel Sengottuvel, Monalisa Hota, Jeongah Oh, Dwight L. Galam, Bernice H. Wong, Markus R. Wenk, Sujoy Ghosh, Federico Torta and David L. Silver, 27 April 2023, The Journal of Clinical Investigation.
DOI: 10.1172/JCI164118