This study carried out a miRNA PCR-array analysis of plasma samples of early-, intermediate- and late-onset FRDA groups, defining a set of 30 differentially expressed miRNAs. Hsa-miR223-3p is the only miRNA shared between the three patient groups and appears upregulated in all of them. The upregulation of hsa-miR223-3p was further validated in all enrolled patients (n = 37, Fc = +2.3; p < 0.0001). Using a Receiver Operating Characteristic (ROC) curve analysis, we quantified the predictive value of circulating hsa-miR223-3p for FRDA, obtaining an AUC (Area Under the ROC Curve) value of 0.835 (p < 0.0001) for all patients. A significant positive correlation between hsa-miR223-3p expression and cardiac parameters in typical FRDA patients (onset < 25 years) was found. Moreover, a significant negative correlation between hsa-miR223-3p expression and HAX-1 (HCLS1 associated protein X-1) at mRNA and protein level was observed in all FRDA patients. In silico analyses suggested HAX-1 as a target gene of hsa-miR223-3p. Accordingly, we report that HAX-1 is negatively regulated by hsa-miR223-3p in cardiomyocytes (AC16) and neurons (SH-SY5Y), which are critically affected cell types in FRDA. This study describes for the first time the association between hsa-miR223-3p and HAX-1 expression in FRDA, thus supporting a potential role of this microRNA as non-invasive epigenetic biomarker for FRDA.

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