High levels of a protein called calnexin in the brain may disrupt the blood-brain barrier of patients with multiple sclerosis, a Canadian study suggests.
The finding could lead to new treatment strategies to prevent brain damage in MS.
The research, “Calnexin is necessary for T cell transmigration into the central nervous system,” was published in the journal JCI Insight.
MS is an autoimmune disease regulated by the actions of white blood cells called T-cells in the brain and spinal cord. When activated, the cells cross the blood-brain barrier to cause inflammation and destroy myelin, which protects nerve fibers. These events lead to the progressive loss of cells and to the manifestations of MS.
Blood-brain barrier disruption is a hallmark of various disorders, including MS. When damaged, the shield no longer prevents the entry of certain cells and large molecules into the central nervous system, which may trigger inflammation and damage to neurons.
Calnexin is a protein found in a cell structure called endoplasmic reticulum (ER). In the ER, calnexin participates in the quality control of newly produced proteins.
In comparison with 10 healthy subjects, the investigators found unexpectedly high levels of calnexin in brain endothelial cells, which are key components of the blood-brain barrier.
Further analysis in mice showed that those lacking calnexin were completely resistant to the development of an MS-like condition called experimental autoimmune encephalomyelitis. The blood-brain barrier of these mice prevented the infiltration of the central nervous system by T-cells.
“These findings identify a link between calnexin expression in CNS [central nervous system] endothelial cells and the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath seen in MS,” the researchers wrote.
“It turns out that calnexin is somehow involved in controlling the function of the blood-brain barrier,” Dr. Marek Michalak, the study’s senior author, said in a press release. “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.”
Researchers now plan to develop a strategy to manipulate the activity of calnexin.
“We think this exciting finding identifies calnexin as an important target for developing therapies for MS. Our challenge now is to tease out exactly how this protein works in the cells involved in making up the blood-brain barrier. 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,” concluded Dr. Luis B. Agellon, a co-author in the study.
Canada has one of the highest rates of MS in the world. It is estimated that one in 340 Canadians have the disease.
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