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Worldwide, about 3 million people are afflicted by multiple sclerosis (MS), an incurable autoimmune disease in which the immune system attacks the fatty membrane (myelin sheath) that insulates the long extensions of nerve cells.
Damaged myelin prevents nerves from communicating with the brain properly, causing symptoms such as blurred vision, difficulty in walking, dizziness and muscular weakness.
Although there are therapies that can slow the progression of the disease — including the drug Copaxone developed at the Weizmann Institute of Science in Israel — the causes for MS onset are still not fully known.
Researchers from Prof. Roy Beck-Barkai’s lab at Tel Aviv University’s School of Physics, in collaboration with researchers from the Technion and the Weizmann Institute (including Prof. Ruth Arnon, one of Copaxone’s co-developers), set out to find how small structural changes in the membranes affect the myelin layer’s function.
In a previous study done in 2016, they found that the myelin sheath’soptimal function as an insulating layer depends on how these membranes are organized.
When functioning at their best, myelin membranes are stacked on top of one another like layers of puff pastry. But sometimes myelin membranes instead are shaped like tubes, and this abnormal structure disrupts function and potentially leads to diseases such as MS.
“After discovering that structural changes in the membranes can affect disease development, we attempted to unveil the factors that may lead to these changes,” Beck explained.
Heat and salt
As physicists, the researchers already knew that temperature and salt concentration may affect the membranes’ molecular structure. They found additional clues supporting this theory, and took them in new directions.
The first clue came from studies showing a possible connection between a high-salt diet and disease progression, and the widely accepted recommendations to MS patients to maintain a balanced diet.
Another clue was found in the work of German doctor Wilhelm Uhthoff. As early as 1890, he observed that MS patients experience vision problems following hot showers or physical exercise. Unthoff therefore used hot baths as a tool for diagnosing the disease.
Clockwise from top left, MS researchers Maor Ram-On, Rona Shaharabani, Roy Beck and Yeshayahu Talmon. Photo courtesy of the Weizmann Institute of Science
To test their hypotheses, the researchers used electron microscopy and x-ray diffraction to examine how changes such as temperature and salt concentrations in the cellular environment affected the structure of the myelin membranes isolated from pig and sheep brains.
They found that a high salt concentration or high temperature (42 degrees Celsius or 107.6 Fahrenheit) in the cellular environment indeed caused the membranes to shift from the normal stacked structure to the deformed tube-like structure.
The researchers believe that this structural change exposes the proteins important for maintaining the normal myelin structure to the immune system, which attacks them and damages the myelin itself.
The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Though the experiments were conducted on membranes in a test tube, their results may mirror the cell changes that take place in a living organism, said Beck.
“These are directions that researchers have not previously looked into,” he said.
“While the cause for the disease is still not completely clear, the new finding takes us one step further to a deeper understanding of its mechanisms. Discoveries like ours further our understanding of the cellular mechanisms that may contribute to the development of diseases like MS, and can form the basis for the search for novel drugs and treatments.”
The study was led by PhD student Rona Shaharabani, and was conducted in collaboration with Prof. Yeshayahu Talmon and PhD student Maor Ram-On from the Technion.
