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. A major challenge in treating neurological diseases is getting drugs across the blood-brain barrier.Essential nutrients like omega-3s require the assistance of dedicated transporter proteins that specifically recognize them and get them across this barrier.

The transporter that lets omega-3s in is called MFSD2A and is the focus of the 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, the team used a technique called single-particle cryo-electron microscopy.

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. Into this map researchers can build a 3D model of the protein, putting each atom in its place.

"Our structure shows that MFSD2A has a bowl-like shape and that omega-3s bind to a specific side of this bowl," explains researcher. "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."

Researchers at Weill Cornell University and Duke- Medical School in Singapore have created a 3D model of the protein, MFSD2A, that shows how the transporter moves and adapts its shape to release omega-3s into the brain. They used the 3D structure as a starting point to run computational simulations that revealed how it works. The team tested and confirmed hypotheses derived from the structure and the computational simulations on how the protein works to pinpoint specific parts of the proteins that are important.

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," the researcher says.

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