Absent CNS protein may protect against MS, open door to new therapies

Wayne Kuznar, for MDLinx | April 24, 2018

Two new discoveries may pave the way for a novel therapeutic strategy in the treatment of multiple sclerosis (MS) that targets the protein calnexin. The first is the finding that high levels of calnexin exist in human brain endothelial cells of patients with MS. The second, from researchers from Canada and the United Kingdom, is that mice that lack calnexin are resistant to experimental autoimmune encephalomyelitis (EAE), an experimental form of human MS. Their studies were published in JCI Insight.

Advertisement

Surprise discovery

Marek Michalak, PhD, MSc, biochemistry professor at the University of Alberta, was part of a research team surprised by their discovery of unusually high levels of calnexin in brain tissue from people with MS. Photo: Melissa Fabrizio, University of Alberta.

Calnexin is an integral membrane protein that is highly expressed during the development of the nervous system. Its involvement in the pathogenesis of MS was examined by investigators who studied human central nervous system (CNS) tissue from persons with and without MS. They then studied mouse models in which the calnexin gene was deactivated.

In examining human CNS tissue from 18 MS cases and 10 persons without MS, they found that calnexin is upregulated in brain samples of patients with MS. When calnexin was deactivated in mice, they became resistant to EAE.

MS is regarded as a progressive autoimmune disease of the CNS, the authors noted, but they did not find evidence of impaired development or function of the immune system in the calnexin-deficient mice.

“In contrast, we observed that the loss of calnexin caused a defect in CNS endothelial cell function that resulted in resistance of the blood-brain barrier to circulating T cell infiltrations,” they wrote. “These findings identify a link between calnexin expression in CNS endothelial cells and the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath seen in MS.”

Co-investigator Marek Michalak, PhD, MSc, distinguished professor of biochemistry at the University of Alberta Faculty of Medicine & Dentistry, Edmonton, Alberta, Canada, stated, “It turns out that calnexin is somehow involved in controlling the function of the blood-brain barrier. This structure usually acts like a wall and restricts the passage of cells and substances from the blood into the brain. When there is too much calnexin, this wall gives angry T cells access to the brain, where they destroy myelin.”

Another co-investigator, Luis Agellon, PhD, BSc, professor, McGill School of Human Nutrition, Quebec, said that the study identifies calnexin as an important target for therapeutic development in MS.

“Our challenge now is to tease out exactly how this protein works in the cells involved in making up the blood-brain barrier,” he said. “If we knew exactly what calnexin does in this process, then we could find a way to manipulate its function to promote resistance for developing MS.”

This study was funded by the Canadian Institutes of Health Research.

Advertisement