Nature: How to break the blood-brain barrier?

The blood-brain barrier, a layer of tightly packed cells arranged in the blood vessels of the brain, can prevent toxins, pathogens and some nutrients from entering the brain.

On June 16, 2021, researchers from Columbia University in the United States, together with the National University of Singapore and the University of Chicago , published an article entitled " Structural basis of omega-3 fatty acid transport across the blood–brain " in the top international journal " Nature ".

The study describes a molecular mechanism that transports Omega-3 to the brain, which may be the key to unlocking the blood-brain barrier and can help researchers develop neurological disease drugs that can better cross the blood-brain barrier

Omega-3 fatty acids are important for the development of the brain and eyes

A protein called MFSD2A is located on the membranes of these endothelial cells and acts as a molecular channel for Omega-3 to cross these barriers

Researchers said that if we know what MFSD2A looks like, we can solve this mystery and use this information to design neuropathy drugs that can hijack this molecular gateway, disguising as Omega-3 fatty acid lysophospholipids, a bit like designing a suitable The key went to observe the lock

To study the structure of MFSD2A, the research team used a technique called single-particle cryo-electron microscopy to cool the sample to a low temperature, observe the molecules on the sub-nanomolar scale, and combine it with new biochemical analysis

The researchers used large-scale atomic assembly molecular dynamics (MD) simulations, and then used advanced computational biophysics methods to analyze the MD data in detail, and obtained a 3D structure diagram of the transporter protein

3D structure of MFSD2A

Structural analysis shows that MFSD2A is in the shape of a bowl, and omega-3 is bound to a specific side of the bowl.

To understand what these movements might look like, the researchers used a 3D model of the protein as a starting point for running computational simulations, revealing how the transporter moves and adjusts its shape to release Omega-3 into the brain

MFSD2A-mediated transport mechanism

Moreover, the researchers also tested and confirmed the assumptions about the working principle of MFSD2A derived from structural and computational simulations to determine the important specific parts of the protein

In short, the blood-brain barrier blocks about 98% of drug absorption, limiting the treatment of neurological diseases

The researchers said that further studies are needed to reveal more details about how MFSD2A mediates the transport of lysophospholipids through the blood-brain barrier

Original source:

Cater, RJ, Chua, GL, Erramilli, SK et al.