Lower-than-usual levels of a molecule called miR126-5p — a type of microRNA, with a role in producing proteins — led to neuron degeneration and disease progression in a mouse model of amyotrophic lateral sclerosis (ALS), in part by working to raise levels of toxic molecules, a study reports.
Its researchers said the work may lead to treatments that target miR126-5p.
The study, “miR126-5p down-regulation facilitates axon degeneration and NMJ disruption via a non-cell-autonomous mechanism in ALS,” was published in the Journal of Neuroscience.
ALS is characterized by the death of motor neurons death and dysfunction of the neuro-muscular junction — the synapse connecting motor nerve cells and muscle fibers — in various parts of the central nervous system, including the cerebral cortex, brain stem, and spinal cord.
microRNAs (miRNAs) are a type of RNA molecule that negatively regulates the expression of its target gene, meaning it works to lower production of the protein that gene is responsible for creating.
miRNAs are also known to play important roles in such cellular processes as neuron growth and retraction, and to be involved in neurodegenerative diseases, including ALS.
A research team sought to further clarify how specific miRNAs might affect the development of ALS.
Using a model of pre-symptomatic ALS male mice, the researchers found a significant decrease in levels of miRNA-126-5p. As expected, the levels of its target genes — the axon destabilizing type-3 Semaphorins (Sema3A) and its receptor Neuropilin1 (NRP1) — were much higher.
Sema3A-induced activity via its receptor NRP1 is considered “axon destabilizing” because it has been shown to induce neuronal cell death. Sema3A levels are found to rise following central nervous system injury and to be higher than usual in several neurodegenerative diseases.
Prior studies, in line with results from this study, suggest that Sema3A/NRP1 plays a toxic role in ALS development and progression.
Researchers next showed that when muscle cells that harbor different ALS-causing mutations are treated with a NRP1 blocking antibody, disease progression in the mice stopped. This further supports the theory that Sem3A expression, regulated by miRNA-126-5p, plays a major role in the neurodegenerative process.
Finally, using both cell and mouse models of the disease, researchers showed that increasing the levels of miR126-5p was sufficient to rescue neuron degeneration.
“We found that the specific overexpression of miR126-5p was beneficial for both axon degeneration and NMJ disruption in vivo in ALS mice models,” Dr. Eran Perlson, lead author of the study, said in a press release. “We were able to pinpoint the fact that alterations in miR126-5p facilitate motor neuron degeneration.”
Also of interest in this study was a discovery that muscle cells, and not just motor neurons, appear to be involved in ALS development.
“We further demonstrated that muscle tissue — not only motor neurons — are undoubtedly involved in the progression of ALS,” Perlson added. “This point is particularly important, as it contradicts other theories in the field.”
The researchers conclude that “miRs [microRNAs] should generally be explored as a potential therapeutic strategy or tool for treatment of ALS and possibly other neurodegenerative diseases,” although possibly only at early disease stages.