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A new discovery paves the way for the development of a treatment for the degenerative disease ALS

Researchers from Tel Aviv University discovered that the motor nerve cells of ALS patients are destroyed by toxins secreted from the muscle, and even found an innovative approach that forms the basis of a possible future drug: a microRNA type molecule silences the genes that cause the toxins to be secreted * The article was published this weekend in the prestigious Journal of Neuroscience

Stephen Hawking at the Science Museum in Jerusalem, December 2006. Photo: Avi Blizovsky
The world famous ALS patient Stephen Hawking (died March 2018) at the Science Museum in Jerusalem, December 2006. Photo: Avi Blizovsky

A groundbreaking development from Tel Aviv University may give new hope to ALS patients - an incurable degenerative disease that gradually paralyzes all the body's muscles, and eventually causes death. Among the famous patients who passed away in recent years: the physicist Stephen Hawking, the industrialist Dov Lautman and the broadcaster Meir Einstein.

The researchers at Tel Aviv University, led by Dr. Eran Perelson from the Faculty of Medicine, are now proposing a new research direction, which may lead to the development of a future cure for ALS. First, they offered an answer to the question of why, of all the types of nerve cells that network our body, ALS specifically damages the motor neurons - those associated with muscles? According to their findings, the muscle cells of ALS patients secrete toxins that damage the nerve cell extensions, thus causing their degeneration and the loss of the connection between them and the muscle cells. Later in the research, they even discovered a molecule that blocks the effect of the toxins, and may form the basis for developing a future drug for the deadly disease.

The research was carried out by the doctoral students Roy Maimon and Ariel Ionescu, the director of the laboratory, Tal Perry and other students from Dr. Perelson's laboratory, in collaboration with Prof. Oded Baher from Hadassah Jerusalem and Miguel Weil from Tel Aviv University. The article was published this weekend in the prestigious Journal of Neuroscience.

"ALS is a violent and fatal degenerative disease, which currently has no effective treatment," says Dr. Perelson. "Mostly it attacks older people, but it can also appear at a young age. The patients gradually lose the ability to move, speak and swallow, and eventually die as a result of paralysis of the muscles of the respiratory system. The paralysis in ALS is caused by the degeneration and death of the motor neurons, which carry commands from the brain to the muscles. The first site affected is the end of the nerve cell extension (axon) at the point of its meeting with the muscle (synapse), but until today the researchers did not understand how and why this happens; And above all: why, of all the nerve cells in the body, are the motor nerve cells specifically damaged? Understanding the mechanisms that cause the disease is an essential infrastructure for the future development of drugs for it."

The level of toxicity has decreased

The first stage of the research was the development of an innovative silicon chip, on which an active system of nerve cells and muscle cells can be grown, and a variety of experiments can be performed on them that cannot be performed inside the living body. Already in the first experiments, the researchers noticed that healthy muscle cells secrete substances that cause the growth of nerve cells, while muscle cells of ALS patients cause the breakdown and degeneration of the nerve cells. From this they concluded that the muscle cells of ALS patients secrete any toxins.

In a scan of all the proteins that a diseased muscle secretes compared to a healthy muscle, an increase in the level of a protein called semaphorin, a toxin, is found, which is known to be active during the development of the nervous system in the fetus - it destroys about 50% of the axons produced by the fetus, which are actually unnecessary. In a normal state, semaphorin is mainly active in the embryonic stage. However, it is known that it reappears in a variety of pathological or traumatic conditions, such as Parkinson's disease and ALS, and after a stroke or spinal cord injury.

Indeed, in another experiment on the chip, the researchers found that the muscle cells of the ALS patients secrete a large amount of semphorin into the junction with the nerve cells, which contributes to the destruction of the nerve cells. An increase in the samphorin receptor, called NRP, was also found in the system. Blocking with an antibody, which prevents the binding between the semaphorin and NRP, resulted in only a partial rescue of the nerve cells. This partial finding did not satisfy the researchers, and they realized that apparently additional toxins are secreted from the muscle.

Following their findings, the researchers searched for a supermolecule that would inhibit all the genes that cause the muscle cells to secrete toxins that destroy the nerve cells. Using advanced genetic sequencing technology, they discovered that toxin levels decrease when there is an increase in the presence of a specific microRNA molecule called miR126. Adding the molecule to the experimental chip led to a great improvement in the condition of the axons. "At this point we decided to move to a living model," says Dr. Perelson. "We injected miR126 into mice in an ALS model, and indeed, we saw an improvement in their condition. The level of toxicity decreased, a benefit was observed in the structure of the cells in the muscle tissue and the nerve-muscle junction (which are destroyed in ALS), and the mice even showed better measures in tests of walking ability.

"We believe that our discovery is a real breakthrough on the way to developing effective drugs for ALS, and later perhaps also for other neurodegenerative diseases, such as Alzheimer's and Parkinson's - in which different types of nerve cells are destroyed," concludes Dr. Perelson. "In addition, the chip we developed may be an effective tool in personalized medicine: it will be possible to extract cells from the patient himself, produce systems on chips from them, and test their response to various drugs. In this way, it will be possible to locate appropriate treatment quickly and efficiently - without exposing the patient to prolonged treatments that are not helpful, and sometimes even cause him harm."

One response

  1. It seems that this is a discovery at the level of the Nobel Prize for Medicine, not to mention the huge commercial potential. nothing short of amazing,

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