Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease with limited treatments. Evidence suggests that reactivation of the HERV-K (HML-2) subgroup contributes to its pathogenesis. This study explores the role of microRNAs (miRNAs) in regulating HML-2 expression. We identified dysregulated miRNAs in ALS and, among them, those predicted to target the HML-2 transcript. The expression levels of selected miRNAs were validated in peripheral blood leukocytes of ALS individuals and healthy controls. Co-transfection experiments were then performed to determine the regulatory potential of these miRNAs on HML-2 expression. We found that the HML-2 envelope gene expression levels were elevated in peripheral blood mononuclear cells of ALS individuals compared to controls (p = 0.02), and they negatively correlated with the levels of previously identified miRNAs, which were downregulated in patients compared to healthy controls (miR-15a-3p, p = 0.04; miR-15a-5p, p = 0.01; miR-150-5p, p = 0.001; miR-182-5p, p = 0.012; miR-192-3p, p = 0.034; miR-221-3p, p = 0.011), except miR-181a-2-3p that was upregulated in ALS compared to controls (p = 0.006). Among these miRNAs, we found, by co-transfection, that miR-182-5p and miR-221-3p were capable of binding the HML-2 transcript. This interaction resulted in a significant downregulation of the expression of its genes, with a pronounced effect observed on the envelope gene. Our findings suggest a link between miRNAs and HML-2 expression. In particular, the observed increase in HML-2 levels in ALS may result from the downregulation of key miRNAs, such as miR-221, that normally help restrain HML-2 expression under physiological conditions.