2 miRNAs Controlling Genes Involved in ALS, and Possible Way of Regulating Them, Identified in Study

2 miRNAs Controlling Genes Involved in ALS, and Possible Way of Regulating Them, Identified in Study
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Sporadic and familial forms of amyotrophic lateral sclerosis (ALS) are associated with two microRNA molecules that are downregulated — meaning these molecules, involved in the protein production of certain genes, cause less protein to be created —, researchers have discovered.

And they found a possible way of “upregulating” these molecules, making them potential therapeutic targets for ALS.

The study, “MicroRNA expression analysis identifies a subset of downregulated miRNAs in ALS motor neuron progenitors,” was published in the journal Scientific Reports.

MicroRNAs, or miRNAs, are tissue-specific small molecules of RNA that negatively regulate the protein production of its target genes. They do this by binding to the gene’s messenger RNA (mRNA) — the molecule generated from DNA that is the template for protein production.

miRNAs are known to play important roles in many important cellular processes, such as maintenance of nerve cell survival and function. Malfunctioning of miRNAs processing and other RNA molecules have been associated with ALS, as well as with other neurodegenerative diseases.

For this reason, identifying deregulated miRNAs in ALS could provide relevant knowledge regarding the disease-associated mechanisms, as well as new targets for potential treatments.

Italian researchers studied miRNA dysregulation in motor nerve cell progenitors (MN) — cells with the potential to generate different types of motor nerve cells — of ALS patients.

They generated motor neuron progenitors from induced pluripotent stem cells (iPSCs) of two sporadic and two familial ALS patients, and two healthy individuals.

iPSCs are stem cells derived from differentiated cells that can virtually generate any cell type in the body.

Cells from both groups of ALS patients showed a significant reduction of 15 miRNAs, compared to those of healthy individuals. These 15 miRNAs were found to target a total of 278 genes.

These genes were associated with disease-relevant mechanisms, including nerve cell processes essential for proper function and nerve cell communication, and injury-associated cell responses.

Further analysis showed that two miRNAs — miR-34a and miR-504, and already linked at reduced levels to neurological disorders — targeted several genes likely involved in ALS.

Among those targets were genes previously associated with motor nerve cell death both in ALS patients and in ALS mouse models, as well as genes involved in nerve cell communication.

These findings supported a link between the low levels of miR-34a and miR-504, and motor nerve cell dysfunction and death in ALS.

Next, the researchers looked at the potential benefits of increasing these miRNA levels in ALS cells by treating derived ALS motor neuron progenitors with enoxacin — an antibiotic shown to raise miRNA levels.  Enoxacin has been designated an orphan drug for ALS by the European Medicines Agency (EMA).

Levels of all identified miRNAs rose, and this change was statistically significant for miR-34a and miR-504. It resulted in a slight increase of ATF3 activity, a gene known to prevent cell death and promote expression of survival and growth-associated genes.

These results suggested that a general increase of miRNAs levels could help in treating ALS, as they regulate key genes involved in disease-associated processes.

“The identification of common downstream genetic pathways controlled by candidate miRNAs can lead to the discovery of pathological mechanisms and the development of therapeutic strategies that target multiple gene networks, increasing the chances of modifying a multifactorial disease such as ALS,” the researchers wrote.

The team noted that larger studies in cells derived from ALS patients must be performed, as well as testing miRNA-based therapies in ALS cells to confirm these findings.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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