Deactivating Protein May Protect Nerve Fibers in MS

Genetically inactivating a protein called cyclophilin D can protect nerve fibers in a mouse model of multiple sclerosis (MS).

Cyclophin D is a key regulator of molecular processes in the nerve cell's powerhouse, the mitochondrion, and can participate in nerve fiber death. Inactivating cyclophilin D strengthens the mitochondrion, helping to protect nerve fibers from injury. The findings were published in the April 2007 issue of the Proceedings of the [US] National Academy of Sciences (PNAS).

The work was carried out by Oregon Health and Science University (OHSU; Portland, OR, USA) researchers, working with colleagues at the Portland Veterans Affairs Medical Center and the University of Padova in Italy. We're extremely excited, said Michael Forte, Ph.D., senior scientist at the Vollum Institute at OHSU and the study's lead author. While we can't genetically inactivate cyclophilin D in people, there are drugs out there that can block the protein. Our research predicts that drugs that block cyclophilin D should protect nerve fibers from damage in MS.

Such a drug would be the first therapy specifically for secondary-progressive MS, one of the more debilitating forms of MS involving an initial period of relapsing and remitting, followed by a steady worsening of symptoms. It affects half of the estimated two million people with MS.
The only available therapies for MS are anti-inflammatory drugs, which reduce the inflammation believed to trigger certain T-cells in the body to attack myelin, the fatty sheath insulating nerve fibers in the brain and spinal cord. The fibers cannot conduct impulses, leading to paralysis, memory loss, dizziness, fatigue, pain, and imbalance. Over time, the nerve fibers themselves degenerate, leading to permanent functional deficits.

All MS drugs available right now are anti-inflammatory, said study co-author Dennis Bourdette, M.D., professor and chairman of neurology in the OHSU School of Medicine, and director of the OHSU MS Center of Oregon. What is desperately needed is a therapeutic that protects the nerve fibers from degeneration.

In recent years, scientists have increasingly viewed MS as a neurodegenerative disorder rather than simply an inflammatory one. Loss of nerve cells, injury to nerve fibers, and atrophy within the central nervous system occur progressively from the start of the disease, eventually leading to permanent disability, especially in patients who have had MS for many years.

What puts people in wheelchairs from MS is not an inflammatory attack on myelin of the central nervous system. It's the severing of the axons [nerve fibers], which is a permanent thing, Dr. Forte said.

Inflammation triggers a chain of molecular events that leads to progressive nerve fiber deterioration in MS, including the development of free radicals such as reactive oxygen and nitrogen that slow the cell's energy generation capability. It also throws off mitochondrial function by causing calcium to build up in the cell, reducing levels of adenosine triphosphate (ATP) that serves as the cell's fuel source.

But scientists believe that cyclophilin D is responsible for causing the unregulated opening of a pore in the mitochondrion's membrane that allows the calcium overload. The OHSU team showed that mice lacking cyclophilin D still developed an MS-like disease, but unlike their counterparts possessing the protein, the mutant mice partially recovered. Scientists found their nerve fibers remained intact, and they resisted the free radicals and calcium overload.
What we've done is make it so the mitochondria can tolerate higher loads of calcium before they die, Dr. Forte said. The mutant mice are protected from axonal damage associated with this MS-like disease in mice.

One class of compounds Forte and Bourdette are especially interested in is non-immunosuppressive derivative of cyclosporin A (CsA). Some nonimmunsuppressive derivatives of cyclosporin A are in human trials for other conditions. Because these drugs are already being evaluated in humans, they could be rapidly tested in MS. Dr. Bourdette believes that a cyclophilin D antagonist could potentially become available as a treatment for MS within five years. We don't have to invent the drugs to target this protein. They already exist, Prof. Bourdette said.


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