Role of mitochondrial lncRNA GAS5 in the pathogenesis of Multiple Sclerosis: interfering with the release of miR-651-5p-enriched exosomes from microglia cells

Multiple Sclerosis (MS) arises from immune system dysfunction and damage to the myelin sheath within the CNS. At various stages of MS, analyzing blood samples has the potential to help differentiate between individuals with MS and those without, detect the early onset of the disease, or distinguish between different types of MS. Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) serves a pivotal role in governing cell growth and arrest, as well as modulating the immune system by acting as the glucocorticoid receptor. This research aims to explore GAS5 expression in peripheral blood mononuclear cells (PBMCs) of Relapsing-Remitting MS (RRMS) patients and evaluate its targeted miRNAs in exosomes. Our findings revealed an elevated expression level of GAS5 in RRMS patients in contrast to control groups (P-value = 0.0121), and GAS5 demonstrated diagnostic potential for RRMS, with an AUC of 0.6498. The in-silico analysis revealed that hsa-miR-651-5p emerged as a central component in the regulatory network of GAS5, with its target genes primarily implicated in transcription and apoptosis regulation. Additionally, RUNX1, YY1, GSK3B, FMR1, and KLF2 were identified as entities linked to GAS5. In this regard, our findings indicate a significant association between redox imbalance and the dysregulation of GAS5 and miR-651-5p expression in the HMC3 cell line. Given the increased expression of miR-651-5p in exosomes under stress, the transport of miR-651-5p into serum exosomes may be varied and related to GAS5 expression in PBMCs of MS subtypes. In conclusion, GAS5 can serve as a mitochondrial marker for RRMS, and redox imbalance appears to influence its regulation, highlighting its role in the cellular stress response. Future research is suggested to focus on elucidating the molecular mechanisms underlying GAS5/miR-651-5p interaction to better understand this process.