Summary:
A research team from Duke-NUS Medical School and the National University of Singapore have found that a transporter protein named Mfsd2a plays a critical role in brain health. The protein protects nerves found in the brain by ensuring they are protected with myelin sheaths which is an insulating layer that encases nerves like plastic would encase the wire of an electrical cord. Having this insulation allows electrical signals to travel quickly and efficiently between nerves and cells. If there is damage to myelin sheaths, nerves may lose their ability to function which is associated with a number of neurological disorders. Myelin sheaths naturally start to degrade during the ageing process, which is why these findings are critically important and may help to reduce the damaging impacts of ageing on the human brain.
Abstract:
Patients with Autosomal Recessive Microcephaly 15 caused by deficiency in the sodium-dependent lysophosphatidylcholine (LPC) transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) present with both microcephaly and hypomyelination, suggesting an important role of LPC uptake by oligodendrocytes in the process of myelination. Here, we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPC) and is critical for oligodendrocyte development. Single cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a KO mice (2aOKO) underwent precocious differentiation into immature oligodendrocytes (iOLs) and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, consistent with microcephaly being consequential to absence of LPC uptake at the blood-brain barrier and not from deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased phospholipids containing omega-3 fatty acids with an opposite increase in unsaturated fatty acids, that latter being products of de novo synthesis governed by Srebp-1. RNA sequencing indicated activation of the Srebp-1 pathway and defective expression of regulators of oligodendrocyte development. Taken together, these findings indicate that the transport of LPCs by Mfsd2a in OPCs is important for maintaining OPC cell state to regulate postnatal brain myelination.
Article Publication Date: 27/04/2023
DOI: 10.1172/JCI164118
