It was a joy to write this perspective together with Marjo van der Knaap. Her deep knowledge of white matter disorders is truly exceptional!

And our paper shows how studying rare diseases can illuminate fundamental brain processes - with implications far beyond! 🧠✨

11/11 < the end >

Identifying the first pathological event in MS matters:

🧪 For better models - most current models are based on triggering an immune attack against myelin...
💊 For better therapies - remyelination is bound to fail if astrocytes can’t support it!!

10/11

This model fits well with beautiful neuropathology studies describing early astrocyte damage in MS lesions.

And with studies showing early myelin abnormalities (swelling, vacuoles, blisters; similar to what we see in MLC) which precede demyelination!

9/11

pubmed.ncbi.nlm.nih.gov/23322421/

We propose a similar mechanism in MS: an immune attack on astrocyte endfeet - triggered by autoimmunity against GlialCAM - disrupts astrocyte homeostasis. Myelin damage follows secondarily, and is a consequence of loss of homeostatic support.

8/11

Genetic defects to these proteins in MLC disrupts endfoot function and disturbs ion and water homeostasis. As a consequence myelin swells and forms vacuoles - not from a direct attack, but because of loss of astrocytic support.

7/11

Astrocytes express GlialCAM as part of a protein complex that is present in the endfeet with which they enwrap blood vessels in the brain. This complex is crucial for brain ion and water homeostasis (and further consists of MLC1, Aquaporin-4 and GPRC5B).

6/11

GlialCAM may not sound familiar - but our lab @amsterdamleuko.bsky.social has studied this astrocyte protein for years in the context of a rare genetic disease called MLC (megalencephalic leukoencephalopathy with subcortical cysts), a childhood-onset white matter disorder (leukodystrophy).

5/11

In trying to fight EBV, the immune system may create antibodies that mistakenly target GlialCAM. Why? Because part of GlialCAM resembles an EBV protein - a case of molecular mimicry.

4/11

www.nature.com/articles/s41...

A clue came in 2022: MS patients can develop antibodies against a protein called GlialCAM - triggered by infection with the very common Epstein-Barr virus (EBV). Nearly all MS patients have had EBV before disease onset.

3/11

Most textbooks describe MS as an immune attack on the fatty myelin layer that insulates axons. But the hunt for a specific myelin antigen in MS hasn’t been very successful… So what’s going on?

2/11

Easy answer: there’s no such thing…

Thanks!

Would love te be added, thanks!