Researchers at Tel Aviv University discovered that Williams patients, a severe and incurable genetic disease also known as 'Love Syndrome', suffer from damage to the myelin that insulates the nerve cells, just like multiple sclerosis patients; The surprising findings may also be relevant to other diseases, including ALS, autism and Alzheimer's
The study was published last night (Monday, 22.4.19) in the journal Nature Neuroscience
Researchers at Tel Aviv University, led by Dr. Boaz Barak from the School of Psychological Sciences and the Sagol School of Neuroscience, discovered that the mechanism that causes the neurological and behavioral deficits that characterize Williams syndrome - a severe genetic disease that currently has no direct treatment - is related to damage to myelin, the substance that envelops and insulates the the nerve cells. The damage to myelin characterizes other diseases, including multiple sclerosis, and the study showed that it is possible that existing drugs for multiple sclerosis may also be effective for Williams syndrome patients, for whom there was no answer until now. In addition, the researchers estimate that the findings may also have significance for other diseases related to myelin damage, such as autism, ALS and Alzheimer's.
The research was carried out in collaboration with Prof. Guoping Peng's laboratory at MIT in the USA. The article was published last night (Monday) in the prestigious journal Nature Neuroscience.
"Williams syndrome is a rare genetic disease, characterized by a variety of physical, cognitive and functional defects; To this day, no direct treatment has been found for it, and the patients are treated with drugs intended for the various symptoms, such as attention deficit disorder, anxiety, physiological injuries and more," explains Dr. Barak. "It has been known for a long time that Williams syndrome is caused by a defect in 25 different genes known to science. Those with the syndrome lack one copy of those genes, out of two that a healthy person has. As of today, there is no treatment for Williams syndrome, and we wanted to investigate in depth its brain mechanisms, with the aim of finding a key to developing a new drug, or alternatively to locating an existing drug that may help patients. We chose to focus on a particular gene called GTF2I, which was suspected in previous studies to be responsible for one of the distinct characteristics of Williams syndrome, also known as 'love syndrome': increased social behavior. We wanted to examine the effect and action of the gene in the nerve cells in certain areas of the cerebral cortex."
In the first step, the researchers created model mice with damage to the GTF2I gene in neurons in the cerebral cortex, which led to damage in motor skills, anxiety and impairments in social behavior. Sequencing the genome of those mice revealed, to the surprise of the researchers, that the injury causes significant damage to myelin - a substance that is an insulating layer that wraps the nerve cells, just like an insulating layer on an electric cable. In the brains of the model mice, a relatively low percentage of nerve cells wrapped in myelin was found, and in the wrapped neurons the myelin layer was much thinner than normal. Damage to myelin, which characterizes a variety of neurological diseases, for example multiple sclerosis, reduces the efficiency of the electrical conduction of the nerve cells, and therefore damages the function of the cells and the communication between them.
"This finding was very surprising, almost an 'earthquake' in scientific terms," says Dr. Barak. "This is because the myelin is not produced by nerve cells, but by supporting cells, which support the nerve cells, and in our model the genes in the supporting cells remain completely normal. Therefore, we concluded from the findings that the damaged nerve cells somehow affect the supporting cells that produce myelin. Indeed, we discovered that the number of mature supporting cells capable of producing myelin was halved in the brains of the model mice."
The damage to the myelin significantly affected the transmission of electrical signals in the brains of the damaged mice: measurements showed that the signals take longer to travel between two different areas of the brain, and the strength of the signals reaching their destination is also relatively low. "Why is it similar? An irrigation pipe has a hole, from which a large part of the water leaks before it reaches the field it is intended to irrigate," says Dr. Barak. Another examination revealed another well-known characteristic of myelin damage: damage to fine motor skills that are controlled by nerve cells that go from the brain to the spinal cord, and in a normal state they are wrapped in a thick layer of myelin.
The surprising findings led the researchers to another step. "For many years, there have been two FDA-approved drugs on the market that are safe to use for multiple sclerosis," says Dr. Barak. "One works 'like masking tape on a perforated pipe', improving the speed of electrical conduction in nerve cells, and the other increases the number of cells that produce myelin, thereby thickening the myelin layer. After realizing that Williams syndrome is related to myelin damage, we decided to try these drugs on our model mice." The two drugs were tried separately, and each of them worked well, restoring the mice's motor skills and social behavior to normal.
To confirm that the finding of myelin damage in Williams syndrome is also relevant to humans, the researchers contacted an international bank for brain tissue used for research, and received brain samples from deceased Williams patients. An in-depth examination of these samples revealed several pieces of evidence supporting the findings: 150 genes whose expression level is significantly lower than the norm, including dozens of genes responsible for myelin production; Myelin thickness is significantly thinner than normal; And the number of supporting cells associated with myelin is significantly smaller than the norm.
"As a result of the research, we better understand the mechanism of Williams syndrome, and we may have even found a medicinal solution for it, which gives hope to patients. In the next step, we will ask to conduct clinical trials in Williams syndrome patients", concludes Dr. Barak. "In addition, we believe that our findings may also have implications for a variety of other diseases related to myelin damage, including ALS, multiple sclerosis, autism, Alzheimer's and other degenerative injuries."
