Researchers identify enzyme as new target for MS myelin repair
Regulating CEMIP could slow disease progression
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- Targeting the enzyme CEMIP with small-molecule inhibitors could promote myelin repair.
- Multiple sclerosis involves myelin damage and insufficient repair.
- CEMIP inhibits myelin repair by blocking oligodendrocyte maturation.
An enzyme called CEMIP could be a target for small-molecule inhibitors that aim to promote myelin repair in people with multiple sclerosis (MS) and other conditions marked by myelin loss, a study found.
Researchers discovered that CEMIP, which is elevated in areas of inflammatory nerve damage in people with MS, produces numerous hyaluronic acid molecules that inhibit the growth of oligodendrocytes, the cells responsible for generating myelin in the brain and spinal cord.
“If we could regulate this enzyme, we might have a handle on promoting [brain and spinal cord] repair,” Larry Sherman, PhD, professor in the Oregon National Primate Research Center at Oregon Health & Science University (OHSU), said in a university news story. “It gives us a better idea of which molecules are worth going after if we want to promote myelin repair.”
The study, “The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation,” was published in ASN Neuro.
In MS, the immune system launches a misguided attack against myelin, a fatty coating that surrounds nerve fibers and is essential for the rapid transmission of nerve signals. Damage to myelin has also been implicated in stroke, brain injuries, and Alzheimer’s disease.
Investigating CEMIP
While the body has some ability to repair damaged or lost myelin, this process is often delayed or insufficient in MS, in part because the growth and maturation of oligodendrocytes is abnormal at sites of inflammatory damage.
This has led researchers to hypothesize that changes in the environment surrounding MS lesions may be contributing to the issue. One such change is the accumulation of hyaluronic acid molecules, which have been shown to block the maturation of oligodendrocyte progenitor cells (OPCs) into fully functional oligodendrocytes, thereby preventing myelin repair.
Previous work from Sherman’s lab showed that MS lesions exhibit elevated levels of CEMIP. More recently, the team found that sulfuretin, a naturally occurring small molecule, inhibits CEMIP activity in live cells and promotes oligodendrocyte maturation.
For the latest study, the researchers sought to further elucidate the mechanisms underlying CEMIP’s involvement in MS and its association with oligodendrocytes using a mouse model of MS.
“This will be important for multiple sclerosis, but it also could be useful [for] Alzheimer’s and probably a lot of other conditions such as stroke or traumatic brain injury where myelin becomes disrupted,” said Sherman, who is also a professor of cell, developmental and cancer biology at the OHSU School of Medicine.
An examination of MS mouse models confirmed the elevated production of CEMIP, hyaluronic acid, and CD44, the primary receptor for hyaluronic acid, during peak periods of inflammation and myelin damage.
Elevated CEMIP production was concentrated in regions of myelin damage in mice and in brain samples from MS patients, and OPCs exhibited the highest CEMIP levels among brain cell types in those regions.
The team found that elevated levels of CEMIP in OPCs, which increased the amount of certain hyaluronic acid molecules, as well as treatment with those hyaluronic acid molecules alone, blocked the maturation of these cells. The data suggested that CEMIP inhibited myelin repair by producing specific fragments of hyaluronic acid.
They injected hyaluronic acid fragments generated from the CEMIP-producing cells into the brains of mice. While control mice showed detectable myelin recovery, animals injected with these hyaluronic acid fragments exhibited delayed myelin repair.
“Our studies have highlighted CEMIP as a tractable target for small molecule inhibitors to accelerate functional remyelination,” the researchers wrote. “We propose that such a strategy has the potential to limit disease progression while promoting [brain and spinal cord] repair, thus reversing neurological impairments for the many patients who live with demyelinating diseases.”
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