Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Structural basis of omega-3 fatty acid transport across the blood–brain barrier

We previously published about this research in a story titled “New Method Could Help Drugs Cross the Blood-Brain Barrier” which can be found here. The study was originally published in the science research journal Nature. You can view the full text of the study here.

This research team was affiliated with Columbia University, and scientists from the New York Structural Biology Center, University of Arizona, and University of Chicago were also involved.

What Happened?

A significant number of rare diseases are illnesses that affect the brain and central nervous system (CNS). Often these are progressive genetic disorders but can include cancers and many others as well. In a lot of cases, the neurological manifestations of these diseases are difficult or even impossible to treat. This is partially due to the presence of the blood-brain barrier. This barrier is present in order to protect the brain from possibly damaging pathogens and toxins. However, it can also block certain nutrients, and many drugs that would normally be promising therapies for neurological diseases can be rendered useless.

This study describes in detail the structure of major facilitator superfamily domain containing 2A (MFSD2A). MFSD2A is able to transport the omega-3 fatty acid docosahexaenoic acid (DHA) across the blood-brain barrier. It must pass the barrier because it is critical for the development and function of the eyes and brain. In describing this structure, the researchers believe that it could be used as a potential mechanism for transporting therapies for neurological disease across the blood-brain barrier. In a sense, MFSD2A could be described as a ‘molecular ferry.’

The three-dimensional structure allowed the scientists to understand how omega-3s like DHA bind to it. The team found that MFSD2A has a total of 12 transmembrane helices:

“The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na⁺-binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry…Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na⁺-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate.”

The researchers used a technique called single-particle cryo-electron microscopy (cryo-EM) to visualize the transporter. This approach suspends the protein molecules in a very thin layer of ice, which is then positioned under an electron microscope. Cameras capture images of the proteins from thousands of different angles.

MFSD2A can be described as bowl shaped, with omega-3s binding to Na+ sites inside of the bowl. The ultimate hope is that therapies can be developed that mimic the behavior of DHA or can be modified to do so.

What is the Blood-Brain Barrier?

The blood-brain barrier is a semipermeable border of endothelial cells that surround blood vessels in the brain and prevent solutes in the blood from crossing into the extracellular fluid where neurons are present. Any molecules or substances that are critical to neurological function are able to pass by various active or passive mechanisms. This structure is already functional at birth. Brain damage and certain diseases such as ALS can affect the function of the barrier. Nanoparticles are a focus of research as they may be able to allow drugs to cross.

Why Does it Matter?

The findings from this study have significant implications for a broad range of rare diseases and disorders that have neurological impacts. Successfully discovering a mechanism that would allow drugs to cross the blood-brain barrier could result in major improvements in outcomes for these rare disease patients. 

While this research is still in its early stages, there is undoubtedly great potential that could come from it.

“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.” – Rosemary J. Cater, Ph.D, research fellow, Columbia University

Several research questions remain, but the insights into the molecular mechanisms that allow MFSD2A to transport DHA is a critical foundation for the structural design of a future neuro-therapy that hijacks this mechanism to cross the blood-brain barrier. The team is continuing its research by trying to determine how MFSD2A is able to initially recognize omega-3s in the bloodstream, another critical piece of information.