The lncRNA GAS5 Is Associated with Altered Exosomal MiR-651-5p Cargo in Microglia and May Serve as a Potential Marker of Relapsing-Remitting Multiple Sclerosis.

Abstract

Introduction: Multiple Sclerosis (MS) involves immune dysfunction and demyelination in the central nervous system. Blood biomarkers can distinguish MS patients and identify early disease. The long non-coding RNA GAS5 regulates cell growth and immune activity. This study examines GAS5 expression in PBMCs of Relapsing-Remitting MS (RRMS) patients and its associated miRNAs in exosomes.

Materials and methods: In this study, we constructed the GAS5-miRNAs-mRNAs regulatory network using data from multiple bioinformatics databases. Peripheral Blood Mononuclear Cells (PBMCs) were isolated from Relapsing-Remitting Multiple Sclerosis (RRMS) patients and healthy controls for expression analysis of GAS5 and related miRNAs using qRT-PCR. Additionally, Human Microglial Cells (HMC3) were subjected to oxidative stress, and GAS5/miRNA expression was evaluated in cells and exosomes to explore redox-related regulatory mechanisms.

Results: Our findings demonstrated significantly higher GAS5 expression levels in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) compared with healthy controls (P = 0.0121). Receiver Operating Characteristic (ROC) analysis further indicated that GAS5 possesses a moderate ability to discriminate RRMS patients from controls, yielding an Area Under the Curve (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 and its derived exosomes.

Discussion: These findings suggest a potential association between redox imbalance and dysregulation of the GAS5/miR-651-5p axis in RRMS. The preferential packaging of miR-651-5p into exosomes under oxidative stress conditions suggests the engagement of redox-responsive regulatory pathways and raises the possibility that exosomal miR-651-5p and GAS5 participate in a coordinated regulatory network contributing to cellular adaptation in RRMS.

Conclusion: GAS5 can serve as a mitochondria-associated regulatory lncRNA for RRMS, and redox imbalance appears to influence its regulation, highlighting its role in the cellular stress response.