Spectacular images of a molecule carrying omega-3 fatty acids in the brain can open a door to administer neurological therapy to the brain.
“We have achieved a three – dimensional structure of the conveyor protein which provides a gateway to omega-3s to enter the brain. In this structure, we can see how omega-3s bind to the transporter. This information may allow the design of drugs that mimic omega-3s to sequester this system and enter the brain, “says first author Rosemary J. Cater, Ph.D., a member of the Simons Society at Mancia Lab University Columbia Vagelos College of Physicians and Surgeons.
The study was published online June 16 in the journal Nature.
A major challenge in the treatment of neurological diseases is to get drugs across the territory blood-brain barrier—A layer of well-packaged cells that covers the blood vessels in the brain and zealously blocks toxins, pathogens and some nutrients that enter the brain. Unfortunately, the layer also blocks many medications that, in turn, are promising candidates for treating neurological disorders.
Essential nutrients such as omega-3s require the assistance of dedicated transporter proteins that specifically recognize them and cause them to cross this barrier. “Carriers are like bouncers in a club, they just let molecules pass by with invitations or behind the scenes,” Cater says.
The carrier 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 attracts omega-3s across the blood-brain barrier can provide us with the information we need to design drugs that can fool this giant and get tickets.”
To visualize MFSD2A, Cater used a technique called a single-particle cryoelectron microscope.
“The beauty of this technique is that we are able to see the shape of the conveyor in detail down to a fraction of a thousandth of a meter,” says study co-leader Filippo Mancia, Ph.D. , associate professor of cell physiology and biophysics at the College of Physicians and Surgeons of Columbia University Vagelos and expert in the structure and function of membrane proteins. “This information is critical to understanding how the conveyor works at the molecular level.”
For cryo-MS analysis, protein molecules are suspended in a thin layer of ice under an electron microscope. Powerful cameras take millions of images of proteins from countless angles that can then be joined together to build a 3D map.
In this map researchers can build a 3D model of the protein, putting each atom in place. “It reminds me of solving a puzzle,” Mancia explains. This technique has become extraordinarily powerful in the visualization of biological molecules in recent years, thanks in part to Joachim Frank, Ph.D., a professor of biochemistry and molecular biophysics at the College of Vagelos Physicians and Surgeons at Columbia University. , which won the Nobel Prize in 2017 for its role in the development of cryoconelectron microscopy data analysis algorithms.
“Our structure shows that MFSD2A has a bowl-like shape and that omega-3s bind to a specific side of that bowl,” Cater explains. “The bowl is upside down and looks inside the cell, but this is just a 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 several different snapshots or, better yet, a moving conveyor film. “
To understand what these movements might look like, a second co-leader of the study, George Khelashvili, Ph.D., 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-3 into the brain. A third co-leader of the study, David Silver, Ph.D., a professor at Duke-NUS Medical School in Singapore and a pioneer in MFSD2A biology, together with his team tested and confirmed hypotheses derived from the structure and computational simulations on how MFSD2A works to identify 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, who used their specific skills to make this project possible.
The team is now investigating how the carrier first recognizes omega-3s in the bloodstream. “But our study has already given us an immense insight into how MFSD2A provides omega-3 to the brain and we’re really excited to see where our results lead,” Cater says.
Rosemary J. Cater et al, Structural bases of the transport of omega-3 fatty acids across the blood-brain barrier, Nature (2021). DOI: 10.1038 / s41586-021-03650-9
Columbia University Irving Medical Center
Citation: Omega-3s may hold the key to unlocking the blood-brain barrier (2021, June 16) recovered on June 16, 2021 at https://medicalxpress.com/news/2021-06-omega-3s-key-blood -brain-barrier. html
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