Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition
Abstract Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic in...
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| Format: | Article |
| Language: | English |
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Springer Nature
2025-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00217-3 |
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| author | Yingbao Zhu Shengwei Xiao Xinxin Guan Haitao Deng Liqiang Ai Kaijing Fan Jin Xue Guangxu Li Xiaoxue Bi Qiao Xiao Yuanjiang Huang Lin Jiang Wen Huang Peng Jin Ranhui Duan |
| author_facet | Yingbao Zhu Shengwei Xiao Xinxin Guan Haitao Deng Liqiang Ai Kaijing Fan Jin Xue Guangxu Li Xiaoxue Bi Qiao Xiao Yuanjiang Huang Lin Jiang Wen Huang Peng Jin Ranhui Duan |
| author_sort | Yingbao Zhu |
| collection | DOAJ |
| description | Abstract Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, we detailed how both genetic and pharmacological inhibition of TDP1 translates to a cascade of beneficial effects, including improved motor functions, amelioration of progressive muscle degeneration, repair of muscle fiber damage, and normalization of aberrant molecular pathology. Remarkably, the TDP1 inhibition led to substantial CCTG repeat contractions, a mechanism that underlies the observed muscle toxicity and neurodegeneration. Our results highlighted the potential of TDP1 as a molecular target for addressing the complex interplay between repeat expansions and neuromuscular degeneration in DM2, hinting at broader applicability in a spectrum of repeat expansion disorders. |
| format | Article |
| id | doaj-art-e09bd7e2b6c74f3ea6a6866dd08119b8 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e09bd7e2b6c74f3ea6a6866dd08119b82025-08-20T03:53:58ZengSpringer NatureEMBO Molecular Medicine1757-46842025-03-0117596799210.1038/s44321-025-00217-3Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibitionYingbao Zhu0Shengwei Xiao1Xinxin Guan2Haitao Deng3Liqiang Ai4Kaijing Fan5Jin Xue6Guangxu Li7Xiaoxue Bi8Qiao Xiao9Yuanjiang Huang10Lin Jiang11Wen Huang12Peng Jin13Ranhui Duan14Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityDepartment of Human Genetics, Emory University School of MedicineFurong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South UniversityAbstract Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, we detailed how both genetic and pharmacological inhibition of TDP1 translates to a cascade of beneficial effects, including improved motor functions, amelioration of progressive muscle degeneration, repair of muscle fiber damage, and normalization of aberrant molecular pathology. Remarkably, the TDP1 inhibition led to substantial CCTG repeat contractions, a mechanism that underlies the observed muscle toxicity and neurodegeneration. Our results highlighted the potential of TDP1 as a molecular target for addressing the complex interplay between repeat expansions and neuromuscular degeneration in DM2, hinting at broader applicability in a spectrum of repeat expansion disorders.https://doi.org/10.1038/s44321-025-00217-3DM2CCTG Repeat ExpansionChemical ScreenTDP1Repeat Instability |
| spellingShingle | Yingbao Zhu Shengwei Xiao Xinxin Guan Haitao Deng Liqiang Ai Kaijing Fan Jin Xue Guangxu Li Xiaoxue Bi Qiao Xiao Yuanjiang Huang Lin Jiang Wen Huang Peng Jin Ranhui Duan Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition EMBO Molecular Medicine DM2 CCTG Repeat Expansion Chemical Screen TDP1 Repeat Instability |
| title | Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition |
| title_full | Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition |
| title_fullStr | Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition |
| title_full_unstemmed | Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition |
| title_short | Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition |
| title_sort | modulating cctg repeat expansion toxicity in dm2 drosophila model through tdp1 inhibition |
| topic | DM2 CCTG Repeat Expansion Chemical Screen TDP1 Repeat Instability |
| url | https://doi.org/10.1038/s44321-025-00217-3 |
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