Plasma miRNAs Correlate with Structural Brain and Cardiac Damage in Friedreich's Ataxia

Friedreich's Ataxia (FRDA) is the most common autosomal recessive ataxia worldwide and is caused by biallelic unstable intronic GAA expansions at FXN. With its limited therapy and the recent approval of the first disease-modifying agent for FRDA, the search for biological markers is urgently needed to assist and ease the development of therapies. MiRNAs have emerged as promising biomarkers in various medical fields such as oncology, cardiology, epilepsy and neurology as well. Cell-free plasmatic miRNAs have potential advantages as biomarkers because of their size, stability against blood RNases, relative ease of obtaining, storage and measurement. In this study, we attempted to characterize the plasma miRNA signature (RNA-Seq followed by qRT-PCR) and its clinical/structural correlates in a cohort of Brazilian patients with FRDA. Our results showed that miR-26a-5p is upregulated and miR-15a-5p is downregulated. The first was correlated with age at onset, cerebellum volume, spinal cord cross-sectional area (C2-CSA) and the left ventricle mass (LV_Mass). For the miR-15a-5p, significant correlations were found with cerebellum volume, spinal cord eccentricity and LV_Mass. It has been previously hypothesized that these miRs target BDNF, modulating its expression and, when this gene is downregulated, it leads to neuronal loss, explaining the ataxic phenotype and our results reinforce this hypothesis. The miR-26a-5p was already associated with cardiomyocyte hypertrophy through the increased NLRP3 inflammasome activity, which is indirectly linked with cardiac hypertrophy. Considering that, we propose these miRNAs as possible prognostic biomarkers for FRDA. However, longitudinal studies are still needed to validate their clinical use.