MicroRNA-653 a Potential Therapeutic Target in Myasthenia Gravis, Mouse Study Shows

A small regulatory RNA, called microRNA-653, inhibited the proliferation of thymus cells, called thymocytes, in a mouse model of myasthenia gravis (MG), a study reports.

Given that the thymus is often abnormally enlarged in MG patients, these results, although preliminary, suggest that microRNA-653 may be a potential therapeutic target for the disease.

The study, “MicroRNA-653 Inhibits Thymocyte Proliferation and Induces Thymocyte Apoptosis in Mice with Autoimmune Myasthenia Gravis by Downregulating TRIM9,” was published in the journal Neuroimmunomodulation.

MicroRNAs (miRs), a special class of short RNA molecules capable of regulating gene expression (protein production), are increasingly recognized for their regulatory role in immune responses. However, their role in diseases like MG remains unclear.

Researchers in this study aimed to investigate the regulatory function of miR-653 on MG and its relationship with the tripartite motif 9 (TRIM9) protein.

They first established a mouse model of MG by transplanting tissue from the thymus of MG patients. The thymus, a gland that is part of the immune system, is linked to the production of antibodies that block the transmission of nerve signals in MG. More than 80 percent of early-onset MG patients have an abnormally enlarged thymus and 10-15 percent of these patients have a tumor in the thymus gland.

After confirming the successful establishment of the mouse model, the researchers saw that the levels of TRIM9, a protein previously linked to inflammation, were significantly higher in thymic tissues of the MG mice compared with control animals that didn’t have the disease. On the contrary, the levels of the microRNA-653 were significantly lower in the thymus of the MG mice relative to controls.

These results led researchers to hypothesize a negative correlation between miR-653 and TRIM9, that is, one increases while the other decreases.

A computer analysis predicted that the miR-653 could potentially target TRIM9. Using an inhibitor of this microRNA, the researchers saw that the levels of TRIM9, both at the levels of messenger RNA and protein, increased. This evidence supports the idea that TRIM9 is a target gene of miR-653 and that its expression is negatively correlated with miR-653 expression in MG mice.

In further experiments, they found that increased levels of the microRNA-653 inhibited proliferation of thymocytes (immune cells in the thymus) and triggered the programmed suicide (a phenomenon called apoptosis) of these cells, a process that could be reverted by increasing the levels (overexpression) of TRIM9.

These results suggest that increasing the levels of microRNA-653 or depleting TRIM9 led to the “inhibition of cell viability, suppression of cell cycle progression, and induction of apoptosis rate in thymocytes,” the researchers wrote, providing evidence of microRNA-653 as a potential therapeutic target for MG.