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However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of \u223c98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.<\/jats:p>","DOI":"10.1242\/dmm.050638","type":"journal-article","created":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T07:57:35Z","timestamp":1715241455000},"source":"Crossref","is-referenced-by-count":10,"title":["An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner"],"prefix":"10.1242","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9352-4908","authenticated-orcid":false,"given":"Eleni","family":"Christoforidou","sequence":"first","affiliation":[{"name":"School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libby","family":"Moody","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5827-6382","authenticated-orcid":false,"given":"Greig","family":"Joilin","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7630-0091","authenticated-orcid":false,"given":"Fabio A.","family":"Simoes","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gordon","sequence":"additional","affiliation":[{"name":"University of Oxford 2 Nuffield Department of Clinical Neurosciences , , Oxford, OX3 9DU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-1697","authenticated-orcid":false,"given":"Kevin","family":"Talbot","sequence":"additional","affiliation":[{"name":"University of Oxford 2 Nuffield Department of Clinical Neurosciences , , Oxford, OX3 9DU , UK"},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford 3 , Oxford, OX1 3QU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5262-7150","authenticated-orcid":false,"given":"Majid","family":"Hafezparast","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Sussex 1 Sussex Neuroscience , , Brighton, BN1 9QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"2024053020485404700_DMM050638C1","doi-asserted-by":"publisher","first-page":"W537","DOI":"10.1093\/nar\/gky379","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update","volume":"46","author":"Afgan","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2024053020485404700_DMM050638C2","doi-asserted-by":"publisher","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"eLife"},{"key":"2024053020485404700_DMM050638C3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. 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