Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination

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 for LPC uptake by oligodendrocytes in the process of myelination. Here we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPCs) and is critical for oligodendrocyte development. Single-cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a-KO mice (2aOKO mice) underwent precocious differentiation into immature oligodendrocytes and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, a finding consistent with the notion that microcephaly is the consequence of an absence of LPC uptake at the blood-brain barrier rather than a deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased levels of phospholipids containing omega-3 fatty acids, with a corresponding increase in unsaturated fatty acids, the latter being products of de novo synthesis governed by Srebp-1. RNA-Seq 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 state to regulate postnatal brain myelination.

Randomized Controlled Trial of Intermittent Calorie Restriction in People With Multiple Sclerosis

“…Recent work has shown that circulating LPCs are inversely associated with BMI 44 45 , inflammatory markers including C-reactive protein 45 46 and cardiovascular disease risk 45 . Importantly, transport of polyunsaturated LPCs across the blood brain barrier is essential for brain development and myelin synthesis 47 48 . iCR decreased levels of HexCer and LacCer in iCR compared to control groups may reflect an overall reduction in sphingolipid synthesis associated with improved metabolic health, since these sphingolipids have been associated with increased cardiovascular risk in some 49 , but not all studies 50 .…”

Knockdown of Placental Major Facilitator Superfamily Domain Containing 2a in Pregnant Mice Reduces Fetal Brain Growth and Phospholipid Docosahexaenoic Acid Content

“…Recently, new structural data indicate that the Na + binding site is near the phospholipid headgroup and may act to stabilize the molecule rather than be co-transported across the plasma membrane [23]. Mice deficient in MFSD2a have severe microcephaly, brain DHA deficiency, and learning and memory deficits [18]. Additional support for an important role for MFSD2a in normal brain growth and development include studies of human non-lethal inactivating mutations in MFSD2a, which result in microcephaly, due to reduced white matter volume, and intellectual disability [24].…”

“…In 2014, Nguyen and coworkers reported that Major Facilitator Superfamily domaincontaining 2a (MFSD2a) is expressed in the endothelial cells of the blood-brain barrier and provided evidence that it transports DHA in the form of lysophosphatidylcholine (LPC-DHA) [17]. Mice deficient in MFSD2a have severe microcephaly, brain DHA deficiency, and learning and memory deficits [18]. The role of placental MFSD2a in the delivery of DHA to the fetal brain is currently unknown.…”

Absence of Causal Relationship between Levels of Unsaturated Fatty Acids and Attention-Deficit/Hyperactivity Disorder: Evidence from Mendelian Randomization Study

“…Additionally, the brain tissue contains high levels of Omega-3 PUFAs and Omega-6 PUFAs, which play signi cant roles in various biological processes such as metabolism, neurotransmission, synaptogenesis, and in ammation [12,13]. Some studies suggest that ADHD is linked to changes in the levels and functionality of UFAs in the brain [14,15], while other studies contradict these ndings [16].…”