Target for Treatment of Multiple Sclerosis Shows Damage to Nerve Cells Can Be Reversed

Their findings reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which is called focal axonal degeneration (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early; therefore, the researchers believe that it could serve as a potential target for therapeutic intervention.

The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the body's own tissues instead. One of the most typical examples is MS. MS is a serious disorder in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is frequently characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse.

The team of researchers was led by Prof. Martin Kerschensteiner of the Medical Center of the University of Munich (Germany) and Prof. Thomas Misgeld from the Technical University of Munich (TUM; Germany). "Development of an effective treatment will be a long-term project,” cautioned Prof. 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 study's findings were published online March 27, 2011, in the journal Nature Medicine.

Commonly, it is thought that the primary target of MS is the myelin sheath, an insulating membrane that enwraps axons, and increases the speed of signal transmission. 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 led by Profs. Kerschensteiner and Misgeld set out to define precisely how the damage to the nerve axons occurs. As Prof. Misgeld explained, "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.”

After inoculation with myelin, these mice begin to show MS-like symptoms. But the researchers found 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 focal axonal degeneration (FAD), is responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath. 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,” said Prof. 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.”

However, it takes years to convert findings in basic research into effective therapies. First, the process that leads to disease symptoms must be elucidated in molecular detail. 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 substances are generated 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,” said Prof. Kerschensteiner. The findings of additional studies on human tissues, carried out in collaboration with specialists based at the Universities of Göttingen (Germany) and Geneva (Switzerland), are encouraging. The characteristic signs of the newly discovered mechanism 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.

Even if this turns out to be the case, it would not mean that a new therapy would be ready soon. The agents utilized in the mouse research are not specific enough and not tolerated well enough to be of clinical use. "Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level,” stated Prof. Kerschensteiner. "We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis.”

Related Links:
Medical Center of the University of Munich
Technical University of Munich