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The most common of these, Huntington\u2019s disease (HD), results from expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Since non-coding RNAs have been implicated in the initiation and progression of many diseases, herein we focused on a circular RNA (circRNA) molecule arising from non-canonical splicing (backsplicing) of HTT pre-mRNA. The most abundant circRNA from HTT, circHTT(2-6), was found to be more highly expressed in the frontal cortex of HD patients, compared with healthy controls, and positively correlated with CAG repeat tract length. Furthermore, the mouse orthologue (mmu_circHTT(2-6)) was found to be enriched within the brain and specifically the striatum, a region enriched for medium spiny neurons that are preferentially lost in HD. Transgenic overexpression of circHTT(2-6) in two human cell lines\u2014SH-SY5Y and HEK293\u2014reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within HTT. CircHTT(2-6) overexpression did not alter total HTT protein levels, but reduced its nuclear localisation. As these phenotypic and genotypic changes resemble those observed in HD patients, our results suggest that circHTT(2-6) may play a functional role in the pathophysiology of this disease.<\/jats:p>","DOI":"10.3390\/cells12091337","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T01:32:53Z","timestamp":1683509573000},"page":"1337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Functional Characterisation of the Circular RNA, circHTT(2-6), in Huntington\u2019s Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Laura","family":"Gantley","sequence":"first","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-9736","authenticated-orcid":false,"given":"Brett W.","family":"Stringer","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"},{"name":"Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa M.","family":"Conn","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-5220","authenticated-orcid":false,"given":"Youichirou","family":"Ootsuka","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"},{"name":"Centre for Neuroscience, Human Physiology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan","family":"Holds","sequence":"additional","affiliation":[{"name":"Department of Genetics and Molecular Pathology, SA Pathology, Flinders Medical Centre, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Slee","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamelya","family":"Aliakbari","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"Kirk","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4256-7481","authenticated-orcid":false,"given":"Rebecca J.","family":"Ormsby","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart T.","family":"Webb","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Hanson","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Lin","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4686-1418","authenticated-orcid":false,"given":"Luke A.","family":"Selth","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"},{"name":"Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA 5042, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1376-4515","authenticated-orcid":false,"given":"Simon J.","family":"Conn","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1136\/jnnp.62.5.535","article-title":"Maternal Transmission in Sporadic Huntington\u2019s Disease","volume":"62","author":"Rosich","year":"1997","journal-title":"J. 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