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 design drug molecules that can reach the brain directly and shed light on disruptions that can lead to neurological disorders.
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 family of transporters regulate important cellular functions.
Source: UCLA
Highlights:
- The zebrafish model developed by the 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 needed to move fatty acids around and back through the transporter.
Researchers from UCLA’s David Geffen School of Medicine, UCLA’s Howard Hughes Medical Institute, and the National Institutes of Health have developed a zebrafish model that provides new insights into how the brain acquires omega fatty acids -3 essentials, including docosahexaenoic acid (DHA) and linolenic acid (ALA).
Their findings, published in Nature Communication, have the potential to improve understanding of lipid transport across the blood-brain barrier and disruptions of this process that can lead to birth defects or neurological disorders.
The model may also allow researchers to design drug molecules 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 particularly high in the brain and important for a healthy nervous system.
Infants get DHA from breast milk or formula, and deficiencies in this fatty acid have been linked to problems with learning and memory.
To reach the brain, omega-3 fatty acids must cross 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 return 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 insights into how Mfsd2a transports omega-3 fatty acids into the brain and may allow researchers to optimize drug delivery through this pathway.
The study also provides fundamental insights into how other members of this family of transporters, called the major facilitatory (MFS) superfamily, regulate important cellular functions.
The study was led by Tamir Gonen, Ph.D., of UCLA and Doreen Matthies, Ph.D., of NIH. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Additional funding for the study was provided by the NIH’s National Institute of General Medical Sciences (NIGMS) and the Howard Hughes Medical Institute.
About this neuroscience research news
Author: David Samson
Source: UCLA
Contact: David Sampson – UCLA
Picture: The image is attributed to Ethan Tyler of the NIH Medical Arts
Original research: Free access.
“Lipid turnaround in the omega-3 fatty acid transporter” by Tamir Gonen. Nature Communication
Abstract
Turning lipids into the omega-3 fatty acid transporter
Mfsd2a is the transporter of docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood-brain barrier (BBB). Mfsd2a defects are linked to conditions ranging from behavioral and motor dysfunctions to microcephaly.
Mfsd2a transports long-chain unsaturated fatty acids, including DHA and α-linolenic acid (ALA), which are attached to the zwitterionic head group of lysophosphatidylcholine (LPC).
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 remain unclear.
Here, we report five single-particle cryo-EM structures of denmark rerio Mfsd2a (drMfsd2a): in the inwardly 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 mechanism of lipid-LPC flipping from the outer membrane sheet to the inner membrane 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.