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Current therapies improve patient outcomes but achieve no definite cure, prompting renewed efforts to better understand disease mechanisms. The calcium channel blocker flunarizine improves motor function in Smn-deficient mice and can help uncover neuroprotective pathways. Murine motor neuron-like NSC34 cells were used to study the molecular cell-autonomous mechanism. Following RNA and protein extraction, RT-qPCR and immunodetection experiments were performed. The relationship between flunarizine mRNA targets and RNA-binding protein GEMIN5 was explored by RNA-immunoprecipitation. Flunarizine increases demethylase Kdm6b transcripts across cell cultures and mouse models. It causes, in NSC34 cells, a temporal expression of GEMIN5 and KDM6B. GEMIN5 binds to flunarizine-modulated mRNAs, including Kdm6b transcripts. Gemin5 depletion reduces Kdm6b mRNA and protein levels and hampers responses to flunarizine, including neurite extension in NSC34 cells. Moreover, flunarizine increases the axonal extension of motor neurons derived from SMA patient-induced pluripotent stem cells. Finally, immunofluorescence studies of spinal cord motor neurons in Smn-deficient mice reveal that flunarizine modulates the expression of KDM6B and its target, the motor neuron-specific transcription factor HB9, driving motor neuron maturation. Our study reveals GEMIN5 regulates Kdm6b expression with implications for motor neuron diseases and therapy.<\/jats:p>","DOI":"10.3390\/ijms251810039","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T09:43:13Z","timestamp":1726652593000},"page":"10039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Understanding the Role of the SMN Complex Component GEMIN5 and Its Functional Relationship with Demethylase KDM6B in the Flunarizine-Mediated Neuroprotection of Motor Neuron Disease Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5615-6807","authenticated-orcid":false,"given":"Badih","family":"Salman","sequence":"first","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0378-226X","authenticated-orcid":false,"given":"Emeline","family":"Bon","sequence":"additional","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-2283","authenticated-orcid":false,"given":"Perrine","family":"Delers","sequence":"additional","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Cottin","sequence":"additional","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Pasho","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6966-9720","authenticated-orcid":false,"given":"Sorana","family":"Ciura","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1112-2495","authenticated-orcid":false,"given":"Delphine","family":"Sapaly","sequence":"additional","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-1699","authenticated-orcid":false,"given":"Suzie","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"T3S, INSERM UMR1124, Facult\u00e9 des Sciences Fondamentales et Biom\u00e9dicales, Universit\u00e9 Paris Cit\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and Characterization of a Spinal Muscular Atrophy-Determining Gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1001\/archneurol.2011.74","article-title":"Spinal Muscular Atrophy","volume":"68","author":"Kolb","year":"2011","journal-title":"Arch. 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