A few months back, I sat down to watch the proceedings of the 3rd international Norrie disease conference held in August, 2015 in Boston.
I listened to Dr. Xin Ye’s presentation on Norrin/Frizzled-4 signaling in vascular development and maintenance. This covered research conducted by the Nathans lab at Howard Hughes Medical Institute, John Hopkins University School of Medicine, over a period of many years.
As the presentation inched towards the final few slides, I sat riveted to my seat. One of the results of the research study was making me want to whoop with joy.
No, wait, I thought. Perhaps I’ve got it all wrong. Rewind. Listen to it again.
Nope, I hadn’t made a mistake.
Even so I found it hard to believe. It was time to go online and dig out the research study corresponding to the latter part of the presentation.
If you’re still reading, here is what this is all about:
The Norrie gene (NDP) codes for the protein Norrin. Norrin attaches to another protein called Frizzled-4. The two proteins fit together like a key in a lock. When Norrin attaches (binds) to Frizzled-4, it initiates a pathway called the Wnt/β-catenin signaling pathway. This in turn promotes certain target genes. The genes that Norrin helps activate are implicated in maintaining the blood brain barrier (BBB) (amongst other things).
The blood brain barrier allows substances such as glucose and oxygen to enter the brain but blocks toxic substances from getting into the brain.
What is the blood brain barrier?
Dr. Nathans explains that, normally, the cells which line the inside of blood vessels (endothelial cells) contain permeable "windows" and relatively loose "bolts" connecting the cells together. In the brain and retina, endothelial cells have no "windows" and their "bolts" connect them tightly. "We now know that endothelial cells that make up the blood-brain barrier have to receive signals constantly from nearby brain or retinal cells telling them, 'You're in the brain. Tighten your bolts and close your windows.'" This reinforcement of the endothelial cells is what is known as the blood brain barrier.
Dr. Nathans explains that, normally, the cells which line the inside of blood vessels (endothelial cells) contain permeable "windows" and relatively loose "bolts" connecting the cells together. In the brain and retina, endothelial cells have no "windows" and their "bolts" connect them tightly. "We now know that endothelial cells that make up the blood-brain barrier have to receive signals constantly from nearby brain or retinal cells telling them, 'You're in the brain. Tighten your bolts and close your windows.'" This reinforcement of the endothelial cells is what is known as the blood brain barrier.
[Source: ScienceDaily]
A compromised blood brain barrier leads to neuronal damage and disturbed brain function.
This should explain the cognitive impairment and autistic traits seen in some Norrie cases.
Additionally, as I have seen numerous studies linking blood brain barrier dysfunction to seizures and epilepsy, I’m guessing that the seizures and epilepsy experienced by some Norrie patients are also an outcome of the loss of integrity of the blood brain barrier. Click here to see one such study.
So. Back to the Nathans lab research.
Simply put, this research establishes that supplying Norrin to the brain in adult Norrie mice completely restores the integrity of the blood brain barrier.
In other words, OH MY GOD. This could be the solution to all the brain related problems associated with Norrie disease. (There are lots of other very significant findings of this study, and I hope to bring them up in subsequent blog posts).
Three cheers for the Nathans lab for this brilliant research!
So, um, where is it, this wonder drug?
I have come to understand from Prof. Nathans that this matter is under consideration by the lab, and that the problem which needs resolving is how best to deliver the drug to the brain.
How much longer before we have a viable treatment?
Till next time then,
Meenu.