Omega-3s May Hold Key to Unlocking Blood-Brain Barrier

Spectacular images of a molecule that shuttles omega-3 fatty acids into the brain may open a doorway for delivering neurological therapeutics to the brain.

“We’ve managed to obtain a three-dimensional structure of the transporter protein that provides a gateway for omega-3s to enter the brain. In this structure, we can see how omega-3s bind to the transporter. This information may allow for the design of drugs that mimic omega-3s to hijack this system and get into the brain,” says first author Rosemary J. Cater, PhD, a Simons Society Fellow in the Mancia Lab at Columbia University Vagelos College of Physicians and Surgeons.

The study was published online on June 16 in the journal Nature.

molecular models of the MFSD2A protein in process of transporting omega-3 into the brain
Models of MFSD2A show how the molecule transports omega-3s and other lipids into the brain. Here, two snapshots of MFSD2A show two lipids—LPC 18:3 (left) and omega-3 (right)— inside the transporter's intracellular cavity. Image from Cater, et al. (2021)

A major challenge in treating neurological diseases is getting drugs across the blood-brain barrier—a layer of tightly packed cells that lines the brain’s blood vessels and zealously blocks toxins, pathogens, and some nutrients from entering the brain. Unfortunately, the layer also blocks many drugs that are otherwise promising candidates to treat neurological disorders.

Essential nutrients like omega-3s require the assistance of dedicated transporter proteins that specifically recognize them and get them across this barrier. “The transporters are like bouncers at a club, only letting molecules with invites or backstage passes in,” Cater says.

The transporter—or bouncer—that lets omega-3s in is called MFSD2A and is the focus of Cater’s research. “Understanding what MFSD2A looks like and how it pulls omega-3s across the blood-brain barrier may provide us with the information we need to design drugs that can trick this bouncer and gain entry passes.”

To visualize MFSD2A, Cater used a technique called single-particle cryo-electron microscopy.

“The beauty of this technique is that we’re able to see the shape of the transporter with details down to a fraction of a billionth of a meter,” says study co-leader Filippo Mancia, PhD,  associate professor of physiology & cellular biophysics at Columbia University Vagelos College of Physicians and Surgeons and an expert in the structure and function of membrane proteins. “This information is critical for understanding how the transporter works at a molecular level.”

For cryo-EM analysis, protein molecules are suspended in a thin layer of ice under an electron microscope. Powerful cameras take millions of pictures of the proteins from countless angles which can then be pieced together to construct a 3D map.

cryoEM images of the omega-3 transporter
Multiple 2D images of the omega-3 transporter were obtained with cryo-electron microscopy and used to construct a 3D map of the protein. Image from Cater et al. (2021).

Into this map researchers can build a 3D model of the protein, putting each atom in its place. “It reminds me of solving a jigsaw puzzle,” Mancia explains. This technique has become remarkably powerful in visualizing biological molecules in recent years, thanks in part to Joachim Frank, PhD, professor of biochemistry & molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons, who won the Nobel Prize in 2017 for his role in developing cryo-electron microscopy data analysis algorithms.

“Our structure shows that MFSD2A has a bowl-like shape and that omega-3s bind to a specific side of this bowl,” Cater explains. “The bowl is upside down and faces the inside of the cell, but this is just a single 3D snapshot of the protein, which in real life has to move to transport the omega-3s. To understand exactly how it works, we need either multiple different snapshots or, better yet, a movie of the transporter in motion.”

To understand what these movements might look like, a second co-leader of the study, George Khelashvili, PhD, assistant professor of physiology and biophysics at Weill Cornell Medicine, used the 3D model of the protein as a starting point to run computational simulations that revealed how the transporter moves and adapts its shape to release omega-3s into the brain. A third co-leader of the study, David Silver, PhD, professor at the Duke-NUS Medical School in Singapore and pioneer in MFSD2A biology, together with his team tested and confirmed hypotheses derived from the structure and the computational simulations on how MFSD2A works to pinpoint specific parts of the protein that are important.

The team also included researchers from the New York Structural Biology Center, the University of Chicago, and the University of Arizona, all using their specific skills to make this project possible.

The team is now investigating how the transporter first recognizes omega-3s from the bloodstream. “But our study has already given us tremendous insight into how MFSD2A delivers omega-3s to the brain, and we are really excited to see where our results lead to,” Cater says.

References

More information

Read more about the discovery on the Duke-NUS Medical School and Weill Cornell Medicine websites.

The study is titled “Structural basis of omega-3 fatty acid transport across the blood–brain barrier.” 

Other authors: Geok Lin Chua (Duke-NUS Medical School), Satchal K. Erramilli (University of Chicago), James E. Keener (University of Arizona), Brendon C. Choy (Columbia), Piotr Tokarz (University of Chicago), Cheen Fei Chin (Duke-NUS Medical School), Debra Q.Y. Quek (Duke-NUS Medical School), Brian Kloss (New York Structural Biology Center), Joseph G. Pepe (Columbia), Giacomo Parisi (Columbia), Bernice H. Wong (Duke-NUS Medical School), Oliver B. Clarke (Columbia), Michael T. Marty (University of Arizona), and Anthony A. Kossiakoff (University of Chicago).

The study was supported by funds from the National Institutes of Health (grants R35 GM132120, R21 MH125649, R35 GM128624, and R01 GM117372); the National Research Foundation and Ministry of Health, Singapore; the Simons Society of Fellows; the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine at Weill Cornell Medical College through the 1923 Fund; and the Khoo Postdoctoral Research Fellowship.

David Silver is a scientific founder and advisor of Travecta Therapeutics, which has developed a drug delivery platform that uses MFSD2A transport. All other authors declare no competing interests.