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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 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), and they negatively correlated with the levels of previously identified miRNAs, which were downregulated in patients compared to healthy controls (miR-15a-3p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04; miR-15a-5p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01; miR-150-5p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001; miR-182-5p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.012; miR-192-3p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.034; miR-221-3p,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.011), except miR-181a-2-3p that was upregulated in ALS compared to controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.006). 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.\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-05861-5","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:32:41Z","timestamp":1776421961000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Downregulation of miRNAs Accompanies Increased HERV-K (HML-2) Expression in Amyotrophic Lateral Sclerosis"],"prefix":"10.1007","volume":"63","author":[{"given":"Elena Rita","family":"Simula","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Garcia-Montojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Canu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanna","family":"Chessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Ercoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Ruiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Solla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avindra","family":"Nath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Antonio","family":"Sechi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"5861_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1750-1172-4-3","volume":"4","author":"LC Wijesekera","year":"2009","unstructured":"Wijesekera LC, Leigh NP (2009) Amyotrophic lateral sclerosis. 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