Study implicates enzyme in neurodegenerative conditions

Researchers at Oregon Health & Science University have identified a type of enzyme with a complicated name — cell migration inducing and hyaluronan-binding protein, or CEMIP — is associated with disorders ranging from multiple sclerosis to stroke to neurodegenerative conditions like Alzheimer’s disease.

The next step is to develop a way to target the enzyme to heal or slow the progression of disease.

In a study published in the journal ASN Neuro, researchers describe their path to implicating CEMIP in cell culture, mice and deceased human tissue. Researchers found this specific enzyme is critical in conditions involving the breakdown of myelin, the protective sheath that covers each nerve cell’s axon — the threadlike portion of a cell that transmits electrical signals between cells. Myelin increases the speed of nerve impulses.

Damage to myelin is associated with multiple sclerosis, stroke, brain injuries and certain forms of dementia including Alzheimer’s.

CEMIP breaks down a molecule called hyaluronic acid, which builds up in the brain after damage. When too much hyaluronic acid accumulates, CEMIP forms small hyaluronic fragments that prevent nervous system repair.

“If we could regulate this enzyme, we might have a handle on promoting central nervous system repair,” said senior author Larry Sherman, Ph.D., professor in the Division of Neuroscience at OHSU’s Oregon National Primate Research Center. “It gives us a better idea of which molecules are worth going after if we want to promote myelin repair. This will be important for multiple sclerosis, but it also could be useful Alzheimer’s and probably a lot of other conditions such as stroke or traumatic brain injury where myelin becomes disrupted.”

Scientists previously established CEMIP’s role in producing inflammatory molecules that can promote the survival and progression of cancer cells to form brain tumors.

Thanks to earlier research at OHSU, scientists already have a possible tool to target CEMIP: Research published a year ago identified a natural compound derived from dahlias that inhibits CEMIP.

The new research confirms CEMIP is likely to be the right target.

Researchers found the enzyme is elevated in brain lesions where myelin is damaged in mice and in people with multiple sclerosis who had donated their bodies to science. Studies in cell cultures and in mice showed the enzyme blocks the body’s ability to regenerate damaged myelin by inhibiting the maturation of oligodendrocyte progenitor cells which, in turn, produce oligodendrocytes that generate myelin.

From an evolutionary perspective, Sherman said, CEMIP likely plays a role regulating the brain’s responses to injury.

“It’s probably important for the early stage of injury response, but the problem occurs when it develops into a chronic condition,” he said. “CEMIP is effective at chewing up hyaluronic acid that accumulates in our body as we age but it also has a side effect of inhibiting the body’s ability to regenerate myelin.”

In addition to Sherman, co-authors include Alex Peters, B.S., Kanon Yasuhara, Weiping Su, Ph.D., Steven Matsumoto, Ph.D., Peter Pham, Fatima Banine, Eliana Harris and Stephen A. Back, M.D., Ph.D.

The research was supported by grants MS160144 from the Congressionally Directed Medical Research Programs; RG4843A5/1 and RG-2206-39711 from the National Multiple Sclerosis Society;  the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Office of the Director, all of the National Institutes of Health, Awards R01NS054044, R21AG089920, T32AG055378, and P51OD011092. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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