MicroRNA Known to Be Abundant in ALS Patients May Offer Way of Treating Disease, Study Suggests
The microRNA-218 (miR-218), produced at excessive levels by damaged or dying nerve cells, may be a therapeutic target for amyotrophic lateral sclerosis (ALS), an animal study suggests.
This molecule was found to disrupt the normal function of astrocytes, star-shaped glial cells found throughout the central nervous system (brain and spinal cord; CNS) with important roles in CNS health — including in the response to neuronal injury.
Their study, “Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis,” was published in the journal Brain.
MicroRNAs are small fragments of nucleic acids that are involved in regulating key workings of a cell. Specifically, microRNAs are responsible for regulating the process of transcription — the first step in gene expression, in which DNA is transcribed into messenger RNA. This process is central to the production of proteins.
MicroRNAs are known to be key transcriptional regulators for various cells, including those of the nervous system.
Nerve cells, or neurons, and astrocytes live close to each other in the brain, and exchange information or communicate. Scientists found that astrocytes also provide neurons with essential nutrients and other molecules important to their health and function. Neurons, in turn, work to regulate astrocyte activity.
Researchers at Washington University School of Medicine in St. Louis and Johns Hopkins University School of Medicine in Baltimore investigated the importance of the microRNA-218 to nerve cell-astrocyte communication in a mouse model of ALS.
MiR-218 is known to be present in large amounts in motor neurons, and to be released in excessive amounts by damaged and dying nerve cells in ALS. A “nearly 10-fold elevation in the CSF [cerebral spinal fluid] of end-stage ALS model rats” has been reported to be typical, the study noted.
The research team found that miR-218 produced by these dying neurons is taken up by astrocytes, causing them to produce less of an important transporter protein called the excitatory amino acid transporter 2 (EAAT2).
MiR-218 was not only seen to affect EAAT2 production, but also that of other astrocyte proteins involved in the maintenance of cell function and in neurodegeneration.
To test if the miR-218 was the chief culprit in poor EAAT2 production, scientists blocked its production by damaged nerve cells in a mouse model of ALS.
This inhibition was seen to prevent the loss of EAAT2 and other miR-218-mediated changes in the ALS mice, demonstrating the importance of the miR-218 in the communication between neurons and astrocytes, and especially in astrocytes’ function.
“We demonstrate here that extracellular miR-218 release from dying motor neurons in ALS can be taken up by neighboring astrocytes and negatively affect astrocyte function,” the researchers concluded. “Intervening in miR-218-mediated astrocyte dysfunction has exciting and broad therapeutic implications.”