In people with sclerosis lateral amyotrophic (ALS), changes in neurons appear to activate immune cells. Reducing inflammation could reduce the symptoms of the disease, according to a study led by Chantelle Sephton, a professor at the Faculty of Medicine at Université Laval.
The study was published in Acta Neuropathologica Communications.
Amyotrophic lateral sclerosis (ALS): here's what new research has revealed
ALS is caused by the loss of upper motor neurons, located in the brain, and lower motor neurons, which extend from the spinal cord to the muscles. Using a genetically modified mouse model, Chantelle Sephton and her team found that structural changes in upper neurons occurred before disease symptoms.
The ALS study suggests that these morphological changes send a signal to microglia and astrocytes, the immune cells of the central nervous system. When they arrive, their effect is protective, but if they remain too long they become toxic to neurons.
This reduces synaptic connections between motor neurons in the brain and spinal cord, resulting in reduced synaptic connections with muscles. These changes lead to atrophy and loss of motor function.
Given this correlation between symptoms and immune response, the ALS research team wondered whether it would be possible to restore synaptic connections by blocking inflammation. “We tested a semi-synthetic drug based on Witaferina A, an extract of the Ashwagandha plant, used for thousands of years in traditional Indian medicine,” explains Chantelle Sephton, affiliated with the CERVO Research Center.
The drug blocks inflammation and allows motor neurons to return to normal. “We noticed that neurons regenerate without activated immune cells. The dendrites of motor neurons begin to grow and establish connections again, increasing the number of synapses between motor neurons and muscles,” reports the researcher.
This seems like a promising way to improve ALS symptoms, whether the disease is familial or sporadic as both types are associated with inflammation.
Other diseases in which inflammation plays a role, such as Alzheimer's, could benefit from this approach. and allows motor neurons to return to normal. “We noticed that neurons regenerate without activated immune cells. The dendrites of motor neurons begin to grow and establish connections again, increasing the number of synapses between motor neurons and muscles,” reports the researcher.
Our movements are controlled by multiple neural pathways that connect the brain and spinal cord. In particular, the neurons of the cerebral cortex send commands to the motor neurons of the spinal cord and then to the muscles, thus causing the required movement. This flow of neural information is impaired in amyotrophic lateral sclerosis (ALS), a widespread progressive neurodegenerative disease in which muscles gradually atrophy, making movement and breathing difficult.
A protein called TDP-43 has been found to accumulate abnormally in neurons affected by ALS, leading to the degeneration of these neurons and motor dysfunction.
In patients with amyotrophic lateral sclerosis, symptoms of motor dysfunction usually appear in one part of the body, such as the limbs, and then progress to others. This further suggests that degeneration begins in one type of motor neuron and subsequently spreads to other motor neurons.
Previous studies have highlighted the accumulation of TDP-43 in motor neurons as a co-occurrence with ALS. In light of these seemingly disparate but related findings, researchers at Niigata University's Brain Research Institute couldn't help but wonder: Could TDP-43 be responsible for propagating degeneration in Amyotrophic Lateral Sclerosis?
To answer this question, researchers have developed mouse models of ALS that primarily accumulate TDP-43 in cortical motor neurons, spinal motor neurons, or skeletal muscles. They then examined how TDP-43 in specific motor neurons triggers disease progression to other motor neurons.
“Accumulation of TDP-43 is observed in the majority of ALS patients, but there has been a long-standing debate as to whether it propagates through the motor pathway and causes disease progression,” says the author. senior Dr. Osamu Onodera, professor in the Department. of Neurology, Brain Research Institute of Niigata University.
The researchers found that TDP-43 induced in the cortical neurons of mouse models of ALS caused mild degeneration. They also found that TDP-43 was transported along axons and transferred to oligodendrocytes, non-neuronal cells that support neurons by wrapping axons with a protective layer called myelin to facilitate neuronal signal transmission.
In contrast, TDP-43 induced in spinal motor neurons did not spread to other cortical or spinal neurons but largely induced cell death in motor neurons and other nearby neurons in the spinal cord. Furthermore, it led to severe atrophy of the muscles, which further led to motor dysfunction.
Co-senior author Dr. Masaki Ueno, professor at the same institute, says: “Our findings suggest that the TDP-43 pathogen has multiple properties to propagate degeneration in the motor pathways of Amyotrophic Lateral Sclerosis, possibly by spreading and inducing other toxic events as well as degeneration and inflammation.”
Their data revealed that TDP-43 spreads through neuroglial connections in the motor pathway and causes several pathological events that degenerate the spinal cord, suggesting that TDP-43 has distinct mechanisms for degeneration in disease motor circuits.
“Elucidating the mechanisms of spread of TDP-43 and other propagating pathological events will lead to the development of a new therapeutic approach to prevent disease progression in Amyotrophic Lateral Sclerosis,” concludes first author, Dr. Shintaro Tsuboguchi, assistant professor at the same institute. The results of this study could pave the way for an effective treatment of Amyotrophic Lateral Sclerosis, offering hope to many Amyotrophic Lateral Sclerosis patients around the world.
Further research offers clues to the biology of spinal cord cells that die in amyotrophic lateral sclerosis and other neurodegenerative diseases. A team of researchers supported by the National Institutes of Health has found evidence linking the large cell size and support structure of motor neurons with genes that underlie their vulnerability to degeneration in ALS.
The study produced a catalog (or “atlas”) characterizing the diverse community of cell types within the human spinal cord. By examining gene expression at the single-cell level, researchers identified dozens of cell types in the spinal cord and analyzed their molecular profiles.
They demonstrated the usefulness of the atlas by looking closely at motor neurons, which provide voluntary movement and motor control. Motor neurons, which degenerate and die in ALS, are large cells with a long extension called an axon, up to a meter long, that conduct signals from the spinal cord to the muscle fiber.
The team found that motor neurons are distinguished by a set of genes that may enable the large size of the motor neuron cell body and axon length, but also underlie their vulnerability to degeneration. Their molecular profile has been defined by genes involved in the structure of the cytoskeleton, which gives shape to the cell and organizes the structures inside it; neurofilament genes related to cell size; and genes linked to the onset of the disease.
Further experiments showed that disease-related genes are also enriched in mouse motor neurons. Taking these findings together, the study provides insight into ALS and demonstrates the utility of the spinal cell atlas for studying the disease and possible interventions.
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