Major Facilitator Superfamily Domain-containing protein 2a, known as MFSD2A, has emerged as a significant player in various biological processes. This protein performs a specialized role in transporting certain molecules across cellular barriers. Its proper function is important for overall health, particularly in brain development and well-being.
What is MFSD2A?
MFSD2A is a protein encoded by the MFSD2A gene. It is classified as a member of the Major Facilitator Superfamily (MFS) of membrane proteins, a large group known for transporting substances across cell membranes. Unlike many other members of this family, MFSD2A is considered an atypical solute carrier due to its unique substrate specificity.
This protein is an integral component of cellular membranes. It is primarily found in the endothelial cells that form the blood-brain barrier (BBB), where it is highly expressed. Beyond the brain, MFSD2A is also found in the retina, placenta, liver, and brown adipose tissue.
How MFSD2A Transports Essential Fats
MFSD2A functions as a specialized sodium-dependent lysophosphatidylcholine (LPC) symporter, a type of transporter that moves two different molecules in the same direction across a membrane, using sodium ions as a driving force. Its primary role involves the transport of essential omega-3 fatty acids, specifically docosahexaenoic acid (DHA), which is carried in the form of lysophosphatidylcholine (LPC-DHA). MFSD2A transports DHA when it is attached to LPC, rather than as an unesterified, free fatty acid.
This transporter is particularly selective. At the blood-brain barrier, MFSD2A represents the main pathway through which DHA enters the brain from the bloodstream. The protein achieves this transport through a “flippase” action, inverting the LPC molecule as it moves from the outer to the inner side of the cell membrane.
Beyond the brain, MFSD2A plays a comparable role in other barrier tissues. It is involved in transporting DHA into the retina, ensuring this fatty acid reaches the eye’s photoreceptor cells, which are important for vision. Furthermore, MFSD2A is located in the basal plasma membrane of the syncytiotrophoblast in the placenta, where it mediates the transfer of LPC-DHA from the mother to the developing fetus, supporting healthy fetal growth.
MFSD2A’s Important Role in Brain Development and Health
The transport of DHA by MFSD2A is important for the development and ongoing function of the brain. DHA is an omega-3 fatty acid that is a major structural component of the brain’s lipids, especially within neuronal membranes. Its presence helps maintain the fluidity and flexibility of these membranes, which supports communication between neurons.
DHA is incorporated into membrane phospholipids, influencing the structural integrity of brain cells. This fatty acid actively promotes neurite growth, which is the formation of new axons and dendrites that extend from neurons, expanding their connections. It also supports synaptogenesis, the process by which new synapses, or connections between neurons, are formed, which is fundamental for brain circuitry.
A sufficient supply of DHA, facilitated by MFSD2A, is particularly important during periods of rapid brain growth, such as prenatal development and early childhood. Adequate DHA intake has been associated with positive cognitive outcomes in infants, including improvements in attention, problem-solving abilities, and language acquisition. The protein’s role in ensuring DHA delivery directly impacts the formation of neural pathways and enhances synaptic plasticity, which are processes underlying learning and memory throughout life.
Understanding MFSD2A Dysfunction
When MFSD2A does not function properly, it can lead to neurological consequences. Mutations in the MFSD2A gene, particularly biallelic variants that affect the protein’s function, are known to cause a specific neurological disorder called autosomal recessive primary microcephaly 15 (MCPH15). This condition is characterized by congenital microcephaly, where an infant is born with a significantly smaller head size due to impaired brain development.
Individuals affected by MFSD2A dysfunction often experience severe developmental delays, intellectual disability, and challenges with muscle tone and movement, such as hypotonia and spastic quadriparesis. Brain imaging studies of these patients reveal distinct abnormalities, including reduced white matter volume, enlarged fluid-filled spaces in the brain (ventriculomegaly), and underdevelopment of structures like the corpus callosum, pons, and cerebellum.
The root cause of these issues lies in the impaired ability of the mutated MFSD2A protein to transport essential LPCs, including DHA, into the brain. Studies in mice lacking functional MFSD2A show a marked reduction in brain DHA levels, accompanied by the loss of neurons in regions like the hippocampus and cerebellum, and the manifestation of cognitive deficits. Furthermore, the absence of functional MFSD2A can lead to a compromised blood-brain barrier, increasing its permeability and potentially allowing harmful substances to enter the brain.