A new international study led by Tel Aviv University researchers may pave the way for an effective treatment for amyotrophic lateral sclerosis (ALS), a fatal and currently incurable neurodegenerative disease.
The team uncovered a previously unknown molecular mechanism that drives the progression of ALS and succeeded in neutralizing it using RNA-based gene therapy. "When we added a specific RNA molecule to human cells and animal models for ALS, the nerve cells stopped degenerating and even regenerated," the researchers said. The breakthrough findings may offer new hope to millions of patients worldwide.
Uncovering the Mechanism Behind ALS
The study was conducted in the laboratory of Prof. Eran Perlson from the Gray Faculty of Medical & Health Sciences and the Sagol School of Neuroscience at Tel Aviv University. It was led by Dr. Ariel Ionescu and Dr. Lior Ankol, in collaboration with Dr. Amir Dori, Senior Neurologist and Head of the Neuromuscular Disease Unit at Sheba Medical Center. Additional participants included researchers from the Weizmann Institute of Science, Ben-Gurion University of the Negev, and research institutions in France, Turkey, and Italy. The paper was published in the leading neuroscience journal Nature Neuroscience.
Prof. Perlson explains: "Our lab studies ALS - a fatal, incurable neurodegenerative disease. ALS affects motor neurons and causes gradual paralysis of all muscles in the body. Most patients die within 3-5 years of diagnosis, due to paralysis of the diaphragm muscles and respiratory failure. We know that in ALS, the neuromuscular junctions - where nerve fibers (axons) meet muscle cells and transmit electrical signals from the brain to the muscles - are disrupted. However, the molecular mechanisms causing this damage remained unknown until now, and consequently no effective treatment has been developed. In this study, we wanted to get to the root of the matter and generate new knowledge that would enable the development of effective drugs for ALS."
Illustration showing the gene therapy's protective effect on motor neurons, preventing the "fire-like" degeneration characteristic of ALS
How the Disease Develops
The current study was based on a feature of ALS discovered previously in Prof. Perlson's lab: toxic clusters (aggregates) of a protein called TDP-43 (usually responsible for regulating protein production at the site) form at the tip of the nerve, where it meets the muscle. To discover how these TDP-43 aggregates are formed, the researchers used a mouse model for ALS, tissues from ALS patients, and cultures of human stem cells.
The study found that muscle cells produce small RNA molecules called microRNA-126 and send them in vesicles, through the synapsis, to the tip of the nerve cell. The role of these molecules is to prevent the expression of the TDP-43 protein at the neuromuscular junction when it is not needed. Dr. Ionescu explains: "We discovered that in ALS, the muscle produces a smaller amount of microRNA-126, which leads to an excess of TDP-43. The excess protein forms toxic aggregates that attack molecules essential for functioning of the mitochondria - the nerve cell's powerhouse. Damage to the mitochondria causes an energy deficit, gradually destroying motor neurons and leaving patients' muscles paralyzed."
Reversing the Degeneration
The study further showed that when the amount of microRNA-126 is reduced, a process similar to ALS occurs, and the neurons are destroyed. Conversely, increasing the level of microRNA-126 in tissues taken from ALS patients and in ALS model mice led to a decrease in the levels of TDP-43, and the neurons stopped degenerating and even regenerated. The researchers concluded that adding microRNA-126 rescues neurons damaged by ALS, prevents degeneration of the neuromuscular junction, and could serve as a basis for developing effective drugs for this currently incurable disease.
Prof. Perlson concludes: "In this study, we identified for the first time a critical molecular mechanism of ALS in its early stages: a reduction in the amount of microRNA-126 transferred from muscle to nerve, resulting in the formation of toxic aggregates of the TDP-43 protein that kill neurons. Our findings may serve as a basis for developing an effective gene therapy focused on adding microRNA-126, which could bring hope to millions of patients and their families around the world."
