Multiple Sclerosis is one of the most common inflammatory diseases of the central nervous system. More than 200,000 patients live with the disease in Germany. As the team led by Professor Martin Kerschensteiner, Director of the Institute of Clinical Neuroimmunology at the LMU, and TUM Professor Thomas Misgeld from the Institute of Neuronal Cell Biology have now discovered, the extent of permanent disability depends on the degree of destruction of the long nerve cell processes – also known as axons.
Cracks in the cell membrane
In the animal model of Multiple Sclerosis, the scientists were able to identify a mechanism that can lead to the death of the axons. According to the researchers, tiny cracks in the cell membrane are responsible for the fact that more calcium can penetrate. According to the studies, a high calcium content apparently increases the risk of nerve cell processes dying off.
In earlier studies, scientists found that axons near inflammatory lesions often swell. A lesion is an injury to or disruption of the function of an organ or limb. Axons may die as a result. But: “Some axons recover spontaneously and swell again,” says Kerschensteiner. “The process is therefore basically reversible and could possibly be influenced therapeutically if we gain a better understanding of the mechanisms.
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High calcium content
In an animal model, the scientists used an in-vivo microscopy approach to show that the development of axons depends on their calcium content. Axons that have an elevated calcium level have a higher risk of swelling. According to the researchers, the chances of their swelling decreasing again are low. Even axons that are not yet swollen already have a higher calcium content. About half of swollen nerve cell processes show high calcium levels. The risk that they die is therefore very high.
Defects in the cell membrane
The calcium comes from the extracellular space. It is located outside the cells and is filled with tissue fluid and extracellular matrix. The calcium penetrates the axon through tiny cracks in the cell membrane. The scientists have demonstrated this with a fluorescent dye coupled to a macromolecule. Normally, the dye is too large to penetrate into an intact axon. If the membrane is damaged, the nerve cell process changes colour. “Using in-vivo microscopy, we were also able to observe that the axons that absorb the dye also show an increased calcium content,” said Kerschensteiner. Misgeld adds that the fact that cracks in the cell membrane can also contribute to the death of nerve fibres in the inflamed nervous system is a new finding that might also be therapeutically relevant in the future.
Cracks can heal
Based on their study results, the researchers now have the hope that new therapeutic approaches for the treatment of Multiple Sclerosis would be possible. This is only possible if it is possible to find out how cracks can be healed. Studies of spinal cord injuries have shown that nerve fibres can heal again – at least if they are the result of mechanical injuries. These findings and the new research results could provide an important basis for new forms of therapy.
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