A Tel Aviv University (TAU) research group has discovered the biological mechanism causing nerve destruction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease. The groundbreaking study suggests that the course of this fatal disease can be delayed and even reversed in its early stages.
The research was led by Professor Eran Perlson and his doctoral students Topaz Altman and Ariel Ionescu and was conducted in collaboration with Dr. Amir Dori, director of the clinic for neuro-muscular diseases at Sheba Medical Center. The results of the study were published in Nature Communication.
ALS is the most common type of motor neuron disease, causing paralysis and muscle atrophy. One out of every 400 people will have the disease, and it has no effective cure. ALS patients gradually lose their ability to control their voluntary muscle movements, leading to complete paralysis and eventually the inability to breathe independently. The average life expectancy of ALS patients is currently only about three years.
“The paralysis caused by the disease results from damage to the motor neurons, which leads to the degeneration nerve endings and to the loss of muscle innervation,” Professor Perlson explains. “This consequently leads to the degeneration of the nerve and the death of motor neurons in the spinal cord. Until now, we could not understand the basic biological mechanism causing the initial damage behind this vicious cascade.”
To solve the mystery, the researchers focused on a protein called TDP-43, which had been shown in earlier studies to accumulate in unusual amounts and localization in the brains of about 95% of all ALS patients. Professor Perlson and his team revealed a new biological link between the protein’s accumulation and the degeneration of the synapses between the motor neuron endings and the muscles, called neuromuscular junctions, which translate neural commands into physical movements. In a series of experiments performed by the researchers, both in cells of ALS patients and in genetically modified model animals, they discovered that the accumulation of the TDP-43 protein in the neuromuscular junction inhibits the ability to locally synthesize proteins that are essential to mitochondrial activity, which provides the power of fundamental cellular processes. The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and ultimately to the death of the motor neurons.
“The motor neurons are found in the spinal cord and need to reach every muscle in the body in order to operate it,” Professor Perlson says. “One can imagine, for example, an extension cable coming out of the spinal cord and reaching the muscles in the little toe in our foot. These extensions can be as long as one meter in adults and are called axons. In earlier studies, we have shown that, in order to maintain this complex organization, motor neuron axons require an increased amount of energy, particularly in the most remote parts, the neuromuscular junctions.
“In our current study, we focused on a pathological change in TDP-43 that takes place in these axons and at neuromuscular junctions. In a normal motor neuron, this protein is mainly found in the nucleus. We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell, particularly in the neuromuscular junction. We discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of essential proteins to mitochondrial function. The condensation of the protein in neuromuscular junctions results in a severe energy depletion, prevents mitochondrial repair, and consequently leads to the disruption of these junctions, degeneration of the entire ‘extension cable,’ and to the death of motor neurons in the spinal cord.”
To confirm their findings, the TAU researchers decided to use an experimental molecule recently published by a group of researchers from the U.S. developed for another purpose. The researchers proved that this molecule could also disassemble the axonal TDP-43 protein condensates in cells from ALS patients, and that this process improved the ability to produce essential proteins, enhanced mitochondrial activity, and prevented neuromuscular junction degeneration. Additionally, in animal models, the researchers showed that the reversal of TDP-43 accumulation in nerves and neuromuscular junction enabled recovery of degenerated neuromuscular junctions and rehabilitated the diseased model animals almost completely.
“The moment we induced the disassembly of TDP-43 protein condensates, the nerves’ ability to produce proteins was recovered, particularly the synthesis of proteins essential to mitochondrial activity. All this made it possible for the nerves to regenerate,” Professor Perlson concludes. “We were able to prove, through pharmacological as well as genetic means, that motor nerves can regenerate and that patients can have hope. Our discovery can lead to the development of new therapies that could either dissolve the TDP-43 protein condensates or increase the production of proteins essential to mitochondrial function, and thereby heal the nerve cells before irreversible damage occurs in the spinal cord.”
Source: AFTAU