Researchers from Tel Aviv University identified for the first time the biological mechanism that causes the destruction of nerves in the muscular dystrophy disease ALS
ALS is the most common muscular dystrophy in the world. About 1 to 8 cases per 100,000 people will get it, and yet the disease has no effective cure. ALS patients gradually lose the ability to control the muscles of the body, to the point of complete paralysis and the loss of the ability to breathe independently. The average life expectancy for ALS patients is currently only about three years.
"To this day it is not clear what causes the disease", explains Prof. Eran Perelson From the Sackler Faculty of Medicine and the Sagol School of Neuroscience. "Among about 10% of patients we know how to point to genetic mutations, but for the other 90% it is a mystery. The paralysis that characterizes the disease is the result of injury to the motor nerves, an injury that degenerates the nerve endings and disconnects the nerve from the muscle, and develops to the point of the death of the nerve cell itself - but to this day we have not understood the basic biological mechanism that causes the initial injury."
Now, a group of researchers from Tel Aviv University led by Prof. Perelson and doctoral students Topaz Altman and Ariel Ionescu, for the first time deciphered the biological mechanism that causes the destruction of nerves in the degenerative disease ALS. The groundbreaking research shows that it is possible to delay, and even reverse, the course of the severe disease in its early stages. The results of the new study, which was conducted in collaboration with Dr. Amir Dori, director of the neuromuscular disease clinic at Sheba Tel Hashomer Hospital, were published in the prestigious journal Nature Communication.
Focusing on neuromuscular junctions
To solve the mystery, the researchers focused on a protein called TDP-43, which previous studies indicated abnormal accumulation in the brains of about 95% of ALS patients. Prof. Perelson and his team revealed for the first time the biological connection between the accumulation of the protein and the degeneration of the connection points between the motor nerves and muscles, called neuromuscular junctions and responsible for activating the muscle system through neural activity. In muscle biopsies taken from ALS patients, the researchers found that the toxic protein accumulates in close proximity to those neuromuscular junctions even in the early stages of the disease and before the development of severe symptoms. In a series of experiments conducted by the researchers, both in the cells of ALS patients and in genetically engineered model animals, it was found that the accumulation of the TDP-43 protein at the neuromuscular junction impairs the ability to produce proteins that are essential for the activity of the mitochondria - the powerhouse of the cell - and that leads to cell degeneration and, at the end of the process, even death.
"You need to understand the uniqueness of the motor nerve cells," says Prof. Perelson. "These nerve cells sit in the spinal cord and need to reach every muscle in the body to activate it. You can imagine, for example, an extension cable that comes out of the spinal cord and reaches up to our little toe. These are extensions that can even reach a length of a meter in adult humans. In previous studies, we showed that for this reason the motor nerve cells need increased learning of energy, especially in the nerve-muscle junctions that are far from the spinal cord. In the present study, we focused on the pathological change occurring in the neurons in the TDP-43 protein. In a normal nerve cell, this protein is mainly found in the nucleus of the cell. We showed that in ALS, the protein leaves the nucleus and forms aggregates throughout the entire cell, and specifically at the neuromuscular junction. Since the activity of the nerve cells depends on those nerve-muscle junctions, which are at the other end of the 'extension cord', this is of critical importance. We discovered that the aggregates formed by the TDP-43 protein at the nerve-muscle junction trap RNA molecules and prevent the production of proteins that are essential for mitochondrial function. Mitochondria is a cellular organelle responsible for energy production in the cell. The accumulation of the protein TDP-43 in the ends of the nerves prevents it, leading to a lack of energy, and finally to the degeneration of the nerve endings in a process that spreads towards the cells themselves in the spinal cord, until they die."
Catch the problem on the other side
To confirm their findings, the researchers from Tel Aviv University decided to use an experimental molecule recently published by a group of researchers from the USA for a different purpose - the acceleration of nerve regeneration after injury, by breaking down protein clusters in nerve endings. The researchers proved that this molecule is also capable of breaking down the TDP-43 protein aggregates in cells from ALS patients, and that the breaking down improved the ability to produce proteins and mitochondrial activity, and prevented the degeneration of the neuromuscular junction. Furthermore, among the genetically engineered model animals, the researchers showed that by breaking down TDP-43 clusters in nerve endings, degenerated neuromuscular junctions can be retrieved - and the diseased model animals can be restored almost completely.
"As soon as we broke down the TDP-43 protein clusters, the ability to produce proteins of the nerves was restored, and in particular the production of the proteins essential for the activity of the mitochondria. All of these allowed the nerves to regenerate", Prof. Perelson concludes. "We have proven, both through pharmacological and genetic means, that the motor nerves can be regenerated - and that it is possible to give hope to patients. In fact, we located the basic mechanism and also the proteins responsible for disconnecting the nerves from the muscles and their degeneration. This discovery could lead to the development of new drugs that could break down the TDP-43 protein aggregates or increase the production of proteins essential to the mitochondria, thereby healing the nerve cells even before the irreversible destruction in the spinal cord. Actually, we perceive the problem on the other side, at the junction of the nerve with the muscle, and if in the future we can diagnose and intervene in time, it may be possible to interrupt the destructive degeneration of the muscles of ALS patients."
The research is an international collaboration with leading researchers from Germany, France, England and the USA, and Tal Gerdos Perry and Amgad Ibrahim from Prof. Perelson's laboratory also participated in it.
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