The role of hsa-miR-21-5p, hsa-miR-210-3p, hsa-miR-197-3p, hsa-miR-125a-5p and hsa-miR-206-3p as circulating microRNA signatures in amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder distinguished by selective loss of motor neurons. Up to now, robust biomarkers for diagnosis and disease progression are missing. This study aims to examine the expression of hsa-miR-21-5p, hsa-miR-210-3p, hsa-miR-197-3p, hsa-miR-125a-5p and hsa-miR-206-3p, as candidate ALS biomarkers in the cerebrospinal fluid (CSF) and serum. Methods CSF and serum samples were collected from 50 ALS patients, 50 age- and sex-matched healthy controls and 50 disease-controls. The expression of the selected miRNAs was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Associations with clinical parameters, including disease phenotype, amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R) at diagnosis, disease duration and progression rate, were evaluated. Functional enrichment analysis was performed on predicted miRNA target genes using Gene Set Enrichment Analysis (GSEA) with Reactome, Gene Ontology Biological Process and Hallmark gene sets. Results Hsa-miR-210-3p, hsa-miR-206-3p, and hsa-miR-21-5p were upregulated in ALS CSF and serum, whereas hsa-miR-125a-5p was downregulated. Hsa-miR-206-3p and hsa-miR-210-3p correlated with disease duration and progression rate, while hsa-miR-21-5p correlated negatively with ALSFRS-R. No statistically significant results were found for hsa-miR-197-3p, between ALS phenotype and miRNA levels and between miRNA expression in CSF and serum. Functional enrichment analyses revealed biological signals related to cellular stress responses, TP53 signaling, SLIT/ROBO axonal guidance, innate immunity-like programs and tissue remodeling. Conclusions Serum and CSF hsa-miR-210-3p, hsa-miR-206-3p and hsa-miR-21-5p could serve as ALS biomarkers. The functional footprint of the dysregulated miRNAs suggest a stress-driven concept of ALS, involving axonal degeneration, immune activation and neuromuscular remodeling.