The inflammatory reactions seen in multiple sclerosis (MS) can induce a previously unknown type of axonal degeneration, according to research by Martin Kerschensteiner, professor at the Medical Center of the University of Munich, and Thomas Misgeld from the Technical University of Munich. They call it focal axonal degeneration (FAD).
In an animal model of MS, this process is reversible if it is recognized and treated early, the scientists add. "Development of an effective treatment will be a long-term project," cautions Kerschensteiner. "As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates."
The research appeared online March 27 in Nature Medicine. The paper is titled “A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis.”
MS is a serious condition in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. Commonly, it is thought that the primary target of MS is the myelin sheath around axons. However, damage to nerve fibers is also a central process, as whether autoimmune pathology ultimately leads to permanent disability depends largely on how many nerve fibers are damaged over the course of time.
The team set out to define precisely how the damage to the nerve axons occurs. "We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy," Misgeld explains. After inoculation with myelin, these mice begin to show MS-like symptoms.
The researchers found, however, that many axons showing early signs of damage were still surrounded by an intact myelin sheath, suggesting that loss of myelin is not a prerequisite for axonal damage. Instead, a previously unrecognized mechanism, termed FAD, was found to be responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath, according to the scientists.
This process could also help explain some of the spontaneous remissions of symptoms that are characteristic of MS. "In its early stages, axonal damage is spontaneously reversible," says Kerschensteiner. "This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment."
In the case of MS it has already been suggested that reactive oxygen and nitrogen radicals play a significant role in facilitating the destruction of axons. These aggressive chemicals are produced by immune cells, and they disrupt and may ultimately destroy the mitochondria.
"In our animal model, at least, we can neutralize these radicals, and this allows acutely damaged axons to recover," says Kerschensteiner. The results of further studies on human tissues, carried out in collaboration with specialists based at the Universities of Göttingen and Geneva, are encouraging. The characteristic signs of the newly discovered process of degeneration can also be identified in brain tissue from patients with MS, suggesting that the basic principle of treatment used in the mouse model might also be effective in humans.