Circulating miRNA biomarkers for sporadic Amyotrophic Lateral Sclerosis: a systematic meta-analysis and empirical validation

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that occurs as sporadic (sALS) in most cases. The disease is not curable, and its pathogenesis is not understood as yet. Given the intricacy of underlying molecular interactions and heterogeneity of ALS, the discovery of molecules contributing to disease onset and progression will open the way for advancement in prevention and therapeutic intervention. Here we conducted a meta-analysis of 12 circulating miRNA profiling studies using the robust rank aggregation (RRA) method, followed by enrichment analysis. We identified miR-451a and let-7f-5p as meta-signature miRNAs whose targets are involved in critical pathogenic pathways underlying ALS, including FoxO, MAPK, and apoptosis. A systematic review of 7 gene profiling studies elucidated that 241 genes upregulated in sALS circulation with concomitant being targets of the meta-signature miRNAs. Protein-protein interaction network analysis for selected targets revealed the main subcluster is involved in multiple cascades, which eventually leads to apoptosis. Besides, evaluation of relative expression of miRNAs by TaqMan RT-qPCR verified let-7f-5p is significantly downregulated in the plasma of patients. Furthermore, we verified the relative expression of two top-ranked upregulated miRNAs and found miR-338-3p significantly upregulated in ALS patients. Receiver operating characteristic (ROC) analysis indicated that let-7f-5p and miR-338-3p are useful plasms biomarkers for diagnosis and a potential therapeutic target for ALS disease.

Diagnostic Circulating miRNAs in Sporadic Amyotrophic Lateral Sclerosis

“…The results of classification performance, made on single miRNA, on an independent dataset suggested 10 miRNAs (miR-139-5p, miR-193b-1, miR-193b, miR-338-5p, miR-455-3p, miR-3911, miR-3911-1, miR-4687-5p, miR-4745-5p, and miR-4763-3p) as potential single diagnostic biomarkers of sALS. Some of them, such as miR-451 (48), or miR-338-3p (49), have been already associated to sALS by other studies. Moreover, miR-338 was upregulated in the spinal cord of SOD1 G93A mouse mice model, where it could be involved in the regulation of glycogen accumulation (50).…”