Gatekeeper of the Brain — #GeneOTW with Mfsd2a

In 2010, the Department of Homeland Security seized 96 tons of marijuana at the US-Mexico border.1  At airport security checkpoints, the TSA confiscates 40 firearms (often loaded) every week.2  And for as long as anyone can remember, the 700-ft, icy monstrosity that is the Wall, has kept out White Walkers—even if the occasional wildling manages to scale it quite easily.  So what are the properties of an effective barrier?  What are the mechanisms that allow passage to certain things, while restricting everything else?  In the case of the brain, it’s Mfsd2a.

Like the blood brain barrier, the purpose of Hadrian’s Wall was to keep things out. More specifically, this 20-foot wall was built to “separate the Romans from the barbarians” and while considerably less epic than the one in Game of Thrones, was the real-life inspiration for George R.R. Martin’s Wall. (Source: Wikimedia Commons)

One doesn’t ordinarily consider something as vital as one’s own blood to be toxic, but the blood brain barrier (BBB) exists to strictly regulate the exchange of substances from the blood to the brain.  Critical for neural development and function, the BBB protects the brain from invading microbes (like bacteria!), and controls the active transport of essential molecules (like glucose!), all while maintaining a stable environment.  To prevent leakage of substances into the brain, the BBB contains several specialized features:3

• Tight junctions between the endothelial cells that make up blood vessels.
• Low rates of transcytosis, the vesicular transport of molecules from one side of the cell to another.  In the case of the BBB, there’s low transcytosis from the blood-side to the brain-side of the vascular endothelial cells.
• Astrocytes and pericytes that wrap around the surface of blood vessels.

Components of the BBB are depicted in this artist’s representation. Note the astrocytes (in maroon) that surround the blood vessel. (Source: Ben Brahim Mohammed)

While we all should be grateful that the BBB is such an effective gatekeeper, this also means that many drugs cannot cross the BBB to treat brain injury or disease.  Understanding the mechanisms that underlie BBB formation will be critical for effectively (and safely) manipulating the BBB to deliver drugs to the brain.  Recent work toward this aim has identified Mfsd2a as a key regulator of BBB function.

Mfsd2a increased in popularity last month (as measured by BioGPS), likely due to the two high profile papers that elucidated its function in BBB formation & maintenance as well as transport of DHA into the brain.

Found in a screen for BBB-specific genes, Mfsd2a (Major Facilitator Super Family Domain containing 2a) is a transmembrane protein expressed in blood vessels with a BBB.4  Although the specific mechanism remains unknown, Mfsd2a regulates BBB function by limiting transcytosis across the vascular endothelial cells.5  Without Mfsd2a, mice fail to develop a proper BBB, with leakiness continuing through adulthood.6  Overall, Mfsd2a knockout mice exhibit a range of abnormalities:78 

• Reduction in brain size and weight
• Significant post-natal mortality
• Neuronal cell loss
• Motor control deficits
• Cognitive and behavioral deficits (including severe anxiety)

Most generally, this is consistent with the association between BBB breakdown and neurological disorders; however, these deficits also match symptoms of omega-3 fatty acid deficiency!  Omega-3 fatty acids, like DHA, are essential for normal brain development and cognitive function, but since they cannot be synthesized in the brain… must be imported in.  The mechanism of DHA uptake across the BBB was a mystery until recently, when researchers determined that Mfsd2a is the major transporter of DHA into the brain!9   Therefore, Mfsd2a not only maintains the integrity of the BBB, but also selectively regulates uptake of an essential molecule—making it doubly important.

This vintage postcard shows leaping salmon in Alaska. Next time you eat salmon, which is simultaneously delicious and high in DHA, send a quick thanks to the Mfsd2a in your BBB! (Source: Wikimedia Commons)

References:

1. Burnett, John. Drugs Cross the Border by Truck, Free Trade, and Chance. NPR News. Retrieved June 11, 2014, from http://www.npr.org/templates/story/story.php?storyId=131106638 [↩]
2. Bierend, Doug. The TSA’s Instagram Feed Is Terrifying and Totally Awesome. Wired. Retrieved June 11, 2014, from http://www.wired.com/2014/07/tsa-instagram/ [↩]
3. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C. (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501): 507-11. [↩]
4. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C. (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501): 507-11. [↩]
5. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C. (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501): 507-11. [↩]
6. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C. (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501): 507-11. [↩]
7. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C. (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501): 507-11. [↩]
8. Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL, Silver DL. (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509(7501):503-6. [↩]
9. Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL, Silver DL. (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509(7501):503-6. [↩]