Summary: Researchers have developed a zebrafish model that offers new insights into how the brain acquires essential omega-3 fatty acids, including DHA and ALA. Their findings could help in designing drug molecules capable of directly reaching the brain and shed light on disruptions that can lead to neurological conditions.
The study provides detailed images of the structure of Mfsd2a, which transports omega-3 fatty acids into the brain. It shows how Mfsd2a transports these essential fatty acids and how other members of this transporter family regulate important cellular functions.
- The zebrafish model developed by researchers provides new insights into how the brain acquires essential omega-3 fatty acids such as DHA and ALA.
- Scientists did not know precisely how the lipid transporter Mfsd2a transports DHA and other omega-3 fatty acids until this study.
- The study team identified three compartments in Mfsd2a that suggest distinct steps required to move and flip fatty acids through the transporter.
Researchers at the UCLA David Geffen School of Medicine, the Howard Hughes Medical Institute at UCLA and the National Institutes of Health have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA).
Their findings, published in Nature Communications, have the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions.
The model may also enable researchers to design drug molecules that are capable of directly reaching the brain.
Omega-3 fatty acids are considered essential because the body cannot make them and must obtain them through foods, such as fish, nuts and seeds. DHA levels are especially high in the brain and important for a healthy nervous system.
Infants obtain DHA from breastmilk or formula, and deficiencies of this fatty acid have been linked to problems with learning and memory.
To get to the brain, omega-3 fatty acids must pass through the blood-brain barrier via the lipid transporter Mfsd2a, which is essential for normal brain development. Despite its importance, scientists did not know precisely how Mfsd2a transports DHA and other omega-3 fatty acids.
In the study, the research team provides images of the structure of zebrafish Mfsd2a, which is similar to its human counterpart. The snapshots are the first to detail precisely how fatty acids move across the cell membrane.
The study team also identified three compartments in Mfsd2a that suggest distinct steps required to move and flip fatty acids through the transporter, as opposed to movement through a linear tunnel or along the surface of the protein complex.
The findings provide key information on how Mfsd2a transports omega-3 fatty acids into the brain and may enable researchers to optimize drug delivery via this route.
The study also provides foundational knowledge on how other members of this transporter family, called the major facilitator superfamily (MFS), regulate important cellular functions.
The study was led by Tamir Gonen, Ph.D., of UCLA and Doreen Matthies, Ph.D., of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Additional funding for the study was provided by NIH’s National Institute of General Medical Sciences (NIGMS) and the Howard Hughes Medical Institute.
About this neuroscience research news
Original Research: Open access.
“Lipid flipping in the omega-3 fatty-acid transporter” by Tamir Gonen. Nature Communications
Lipid flipping in the omega-3 fatty-acid transporter
Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly.
Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup.
Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear.
Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions.
These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side.
These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.