Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease
Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease (HD), results from expansion of the CAG repeat region in exon...
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MDPI AG
2023-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/9/1337 |
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| author | Laura Gantley Brett W. Stringer Vanessa M. Conn Youichirou Ootsuka Duncan Holds Mark Slee Kamelya Aliakbari Kirsty Kirk Rebecca J. Ormsby Stuart T. Webb Adrienne Hanson He Lin Luke A. Selth Simon J. Conn |
| author_facet | Laura Gantley Brett W. Stringer Vanessa M. Conn Youichirou Ootsuka Duncan Holds Mark Slee Kamelya Aliakbari Kirsty Kirk Rebecca J. Ormsby Stuart T. Webb Adrienne Hanson He Lin Luke A. Selth Simon J. Conn |
| author_sort | Laura Gantley |
| collection | DOAJ |
| description | Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease (HD), results from expansion of the CAG repeat region in exon 1 of the <i>HTT</i> 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 <i>HTT</i> pre-mRNA. The most abundant circRNA from <i>HTT</i>, <i>circHTT(2-6)</i>, 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_<i>circHTT(2-6)</i>) 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 <i>circHTT(2-6)</i> in two human cell lines—SH-SY5Y and HEK293—reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within <i>HTT</i>. <i>CircHTT(2-6)</i> 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 <i>circHTT(2-6)</i> may play a functional role in the pathophysiology of this disease. |
| first_indexed | 2024-03-11T04:21:00Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T04:21:00Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-44403ff8fe62462eb9bb5985f09982662023-11-17T22:44:32ZengMDPI AGCells2073-44092023-05-01129133710.3390/cells12091337Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s DiseaseLaura Gantley0Brett W. Stringer1Vanessa M. Conn2Youichirou Ootsuka3Duncan Holds4Mark Slee5Kamelya Aliakbari6Kirsty Kirk7Rebecca J. Ormsby8Stuart T. Webb9Adrienne Hanson10He Lin11Luke A. Selth12Simon J. Conn13Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaDepartment of Genetics and Molecular Pathology, SA Pathology, Flinders Medical Centre, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaFlinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, AustraliaTrinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease (HD), results from expansion of the CAG repeat region in exon 1 of the <i>HTT</i> 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 <i>HTT</i> pre-mRNA. The most abundant circRNA from <i>HTT</i>, <i>circHTT(2-6)</i>, 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_<i>circHTT(2-6)</i>) 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 <i>circHTT(2-6)</i> in two human cell lines—SH-SY5Y and HEK293—reduced cell proliferation and nuclear size without affecting cell cycle progression or cellular size, or altering the CAG repeat region length within <i>HTT</i>. <i>CircHTT(2-6)</i> 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 <i>circHTT(2-6)</i> may play a functional role in the pathophysiology of this disease.https://www.mdpi.com/2073-4409/12/9/1337circular RNAHuntington’s disease<i>Huntingtin</i><i>HTT</i>triplet repeat disorders |
| spellingShingle | Laura Gantley Brett W. Stringer Vanessa M. Conn Youichirou Ootsuka Duncan Holds Mark Slee Kamelya Aliakbari Kirsty Kirk Rebecca J. Ormsby Stuart T. Webb Adrienne Hanson He Lin Luke A. Selth Simon J. Conn Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease Cells circular RNA Huntington’s disease <i>Huntingtin</i> <i>HTT</i> triplet repeat disorders |
| title | Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease |
| title_full | Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease |
| title_fullStr | Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease |
| title_full_unstemmed | Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease |
| title_short | Functional Characterisation of the Circular RNA, <i>circHTT(2-6)</i>, in Huntington’s Disease |
| title_sort | functional characterisation of the circular rna i circhtt 2 6 i in huntington s disease |
| topic | circular RNA Huntington’s disease <i>Huntingtin</i> <i>HTT</i> triplet repeat disorders |
| url | https://www.mdpi.com/2073-4409/12/9/1337 |
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