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Modulating MicroRNA Expression Offers Potential New Strategy for Treating Multiple Sclerosis

12/13/2019

New research led by Ranjan Dutta, PhD, Department of Neurosciences, and published in Cell Reports demonstrates the importance of controlled microRNA expression for effective remyelination, a process that when hindered can contribute to the onset and progression of multiple sclerosis (MS).

Myelin, the protective coating that covers axons, helps to transmit electrical signals between neurons. When damaged or missing, it is replaced through a processed called remyelination. Oligodendrocytes, specialized cells within the central nervous system, are key players in the remyelination process. They are derived from parental cells called oligodendrocyte progenitor cells (OPCs). As such, through a complex cascade of cellular events, effective maturation and proliferation of OPCs is imperative for remyelination.

In the current study, Dr. Dutta and his collaborators found that dysregulation of microRNA levels—specifically miR-27a—is associated with stalled OPC differentiation and maturation and results in impaired remyelination. In addition to underscoring the importance of a steady state of miR-27a for remyelination, their findings suggest that therapeutics to modulate miR-27a levels may offer a previously unexplored strategy to treat neurological diseases characterized by faulty myelination and demyelination, including MS.

Previous research has shown that microRNAs play an important role in directing oligodendrocyte development, and dysregulated expression of microRNAs has been well documented in the context of MS. How microRNA expression affects specific steps in the OPC to oligodendrocyte process, however, is not currently well defined.

Here, the team focused specifically on miR-27a levels—oligodendrocytes are known to express miR-27a and circulatory miR-27a levels have been closely associated with other severe neurological disorders, including Alzheimer’s disease and amyotrophic lateral sclerosis.

Using CRISPR/Cas-9 gene editing technology, the researchers blocked miR-27a expression and found that miR-27a loss hindered the preliminary phases of oligodendrocyte generation, specifically OPC differentiation and maturation. When miR-27a was administered to a preclinical model, increased levels of the microRNA led to decreased myelination and fewer mature oligodendrocytes. This importantly provides in vitro validation of miR-27a’s inhibitory effect on OPC maturation and proliferation and, ultimately, remyelination.

Ajai Tripathi, PhD, a research associate in the Dutta laboratory, was first author on the study, which was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and the National Multiple Sclerosis Society.



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