A small molecule known as mir-494-3p might play a protective role in the survival of motor nerve cells, a discovery that could lead to the development of new therapies for amyotrophic lateral sclerosis (ALS), a study suggests.
The study, “Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS,” was published in the journal EBioMedicine.
ALS is a rare neurological disease characterized by deterioration of motor nerve cells, or neurons, that control voluntary muscle movement.
There are two types of ALS: familial and sporadic. Most patients have sporadic ALS, while approximately 10 percent have familial ALS. Most patients who develop familial ALS have mutations in the C9ORF72 gene.
While ALS is caused by the deterioration of motor neurons, studies have shown that astrocytes also play a role in disease progression. In fact, researchers have isolated astrocytes from ALS patients and shown that these cells can be toxic to normal motor neurons in the context of disease.
Previous studies have shown that astrocytes play a role in regulating nerve cell function, which is regulated, in part, through the secretion of extracellular vesicles. Extracellular vesicles are essentially cargo ships filled with small molecules that are secreted from a cell (in this case, an astrocyte) and are involved in cell-cell communication (in this case, with motor neurons).
At this point, it is not very well-understood how astrocytes contribute to ALS, but researchers hypothesize that there may be irregularities in the extracellular vesicles that are released by astrocytes. The cargo carried by these extracellular vesicles includes small molecules known as microRNAs (miRNAs), which have also been implicated in ALS.
Researchers in this study sought to determine whether extracellular vesicles secreted from astrocytes of ALS patients have altered levels of specific miRNAs that could result in toxicity toward motor neurons.
For this purpose, the researchers used human-induced astrocytes from three ALS patients with mutations in the C9ORF72 gene, as well as from three healthy individuals, and grew these cells in a culture (in a lab). Astrocyte-derived extracellular vesicles were then extracted from the culture and exposed to mouse motor neurons.
First, the researchers showed that the formation of extracellular vesicles, as well as the miRNA cargo in them, were not regulated properly in the astrocytes of patients with ALS, which translated into impaired motor neuron survival.
Specifically, they discovered there was a reduction in levels of an miRNA called miR-494-3p, which regulates levels of semaphorin 3A (SEMA3A), a protein involved in motor neuron death. As a result, motor neurons exposed to low levels of miR-494-3p had higher than normal levels of Sema3a and experienced increased cell death.
By restoring the levels of miR-494-3p, the researchers were able to reduce the levels of Sema3A in motor neurons and increase their survival.
“When an artificial form of miR-494-3 was introduced to the astrocyte-motor neuron culture, the survival of neurons was significantly improved,” Laura Ferraiuolo, PhD, from University of Sheffield’s Institute of Translational Neuroscience and lead author of the study, said in a press release.
Additionally, the researchers looked at expression of mir-494-3p in brain and spinal tissue isolated from patients with sporadic ALS. They found that mir-494-3p was also lower in these patients, which supports the idea that mir-494-3p plays an important role in both types of ALS and could potentially hold therapeutic possibilities.
“The study shows that restoring depleted micro-RNAs can improve cell survival. The results not only shed more light on the mechanisms of this complex disease, but they hold massive potential for the identification and development of new therapies for ALS and other neurodegenerative diseases,” Ferraiuolo said.