Fluorescence microscopy could advance multiple sclerosis treatment

March 29, 2011

A team of researchers reveals that the inflammatory reaction in multiple sclerosis (MS) can induce a previously unknown type of axonal degeneration. Setting out to define precisely how the damage to the nerve axons occurs, the researchers observed via fluorescence microscopy a subset of axons genetically marked with a fluorescent protein. Upon doing so, they discovered that the degenerative process—called focal axonal degeneration—is reversible if it is recognized and treated early.

After inoculation with myelin, the animal model used by the researchers began to show MS-like symptoms. But they 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, the aforementioned 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," says Martin Kerschensteiner of the Medical Center of the University of Munich. "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 transform novel 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 chemicals are produced by immune cells, and they disrupt and may ultimately destroy the mitochondria. Mitochondria are the cell's powerhouses because they synthesize ATP, the universal energy source needed for the build-up and maintenance of cell structure and function.

"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.

Even if this turns out to be the case, it would not mean that a new therapy would soon be at hand. The chemical agents used in the mouse experiments 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," says Kerschensteiner. "We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis."

The work received generous support from the Deutsche Forschungsgemeinschaft (DFG) and the Emmy Noether Program. The Hertie Foundation and the Alexander von Humboldt Foundation also contributed significantly to financing the project. The study was performed within the framework of the Center for Integrated Protein Science Munich (CIPSM) – a Cluster of Excellence – and the Multiple Sclerosis Competence Network set up by the Federal Ministry for Research and Technology.

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Posted by Lee Mather

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