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Mol. Life Sci."],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>N6-methyladenosine (m6A) regulates many aspects of RNA metabolism and is involved in learning and memory processes. Yet, the impact of a dysregulation of post-transcriptional m6A editing on synaptic impairments in neurodegenerative disorders remains unknown. Here we investigated the m6A methylation pattern in the hippocampus of Huntington\u2019s disease (HD) mice and the potential role of the m6A RNA modification in HD cognitive symptomatology. m6A modifications were evaluated in HD mice subjected to a hippocampal cognitive training task through m6A immunoprecipitation sequencing (MeRIP-seq) and the relative levels of m6A-modifying proteins (FTO and METTL14) by subcellular fractionation and Western blot analysis. Stereotaxic CA1 hippocampal delivery of AAV-shFTO was performed to investigate the effect of RNA m6A dysregulation in HD memory deficits. Our results reveal a m6A hypermethylation in relevant HD and synaptic related genes in the hippocampal transcriptome of <jats:italic>Hdh<\/jats:italic><jats:sup>+<jats:italic>\/Q111<\/jats:italic><\/jats:sup> mice. Conversely, m6A is aberrantly regulated in an experience-dependent manner in the HD hippocampus leading to demethylation of important components of synapse organization. Notably, the levels of RNA demethylase (FTO) and methyltransferase (METTL14) were modulated after training in the hippocampus of WT mice but not in <jats:italic>Hdh<\/jats:italic><jats:sup>+<jats:italic>\/Q111<\/jats:italic><\/jats:sup> mice. Finally, inhibition of FTO expression in the hippocampal CA1 region restored memory disturbances in symptomatic <jats:italic>Hdh<\/jats:italic><jats:sup>+<jats:italic>\/Q111<\/jats:italic><\/jats:sup> mice. Altogether, our results suggest that a differential RNA methylation landscape contributes to HD cognitive symptoms and uncover a role of m6A as a novel hallmark of HD.<\/jats:p>","DOI":"10.1007\/s00018-022-04444-6","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T15:29:20Z","timestamp":1657639760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington\u2019s disease mice"],"prefix":"10.1007","volume":"79","author":[{"given":"Anika","family":"Pupak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sancho-Balsells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Alcal\u00e1-Vida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Espina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Giralt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eul\u00e0lia","family":"Mart\u00ed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf Andersson Vang","family":"\u00d8rom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Gin\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-0708","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Brito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"4444_CR1","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1002\/ana.410370516","volume":"37","author":"T Foroud","year":"1995","unstructured":"Foroud T, Siemers E, Kleindorfer D et al (1995) Cognitive scores in carriers of Huntington\u2019s disease gene compared to noncarriers. 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