MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by the selective loss of spinal motor neurons (MNs) and concomitant muscle weakness. Mutation of SMN1 is known to cause SMA, and restoring SMN protein levels via antisense oligonucleotide treatment is effective for ameliorati...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123000641 |
| _version_ | 1797854321925160960 |
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| author | Tai-Heng Chen Shih-Hsin Chang Yu-Fu Wu Ya-Ping Yen Fang-Yu Hsu Yen-Chung Chen Yang Ming Ho-Chiang Hsu Yi-Ching Su Sheng-Tang Wong Jui-Hung Hung Shih-Hwa Chiou Yuh-Jyh Jong Jun-An Chen |
| author_facet | Tai-Heng Chen Shih-Hsin Chang Yu-Fu Wu Ya-Ping Yen Fang-Yu Hsu Yen-Chung Chen Yang Ming Ho-Chiang Hsu Yi-Ching Su Sheng-Tang Wong Jui-Hung Hung Shih-Hwa Chiou Yuh-Jyh Jong Jun-An Chen |
| author_sort | Tai-Heng Chen |
| collection | DOAJ |
| description | Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by the selective loss of spinal motor neurons (MNs) and concomitant muscle weakness. Mutation of SMN1 is known to cause SMA, and restoring SMN protein levels via antisense oligonucleotide treatment is effective for ameliorating symptoms. However, this approach is hindered by exorbitant costs, invasive procedures, and poor treatment responses of some patients. Here, we seek to circumvent these hurdles by identifying reliable biomarkers that could predict treatment efficacy. We uncovered that MiR34 exhibits consistent downregulation during SMA progression in both human and rodent contexts. Importantly, Mir34 family-knockout mice display axon swelling and reduced neuromuscular junction (NMJ) endplates, recapitulating SMA pathology. Introducing MiR34a via scAAV9 improved the motor ability of SMNΔ7 mice, possibly by restoring NMJ endplate size. Finally, we observed a consistent decreasing trend in MiR34 family expression in the cerebrospinal fluid (CSF) of type I SMA patients during the loading phase of nusinersen treatment. Baseline CSF MiR34 levels before nusinersen injection proved predictive of patient motor skills 1 year later. Thus, we propose that MiR34 may serve as a biomarker of SMA since it is associated with the pathology and can help evaluate the therapeutic effects of nusinersen. |
| first_indexed | 2024-04-09T20:04:06Z |
| format | Article |
| id | doaj.art-420741cfadc04cd1856eed780b37a795 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-09T20:04:06Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-420741cfadc04cd1856eed780b37a7952023-04-02T06:12:51ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-06-0132144160MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA miceTai-Heng Chen0Shih-Hsin Chang1Yu-Fu Wu2Ya-Ping Yen3Fang-Yu Hsu4Yen-Chung Chen5Yang Ming6Ho-Chiang Hsu7Yi-Ching Su8Sheng-Tang Wong9Jui-Hung Hung10Shih-Hwa Chiou11Yuh-Jyh Jong12Jun-An Chen13PhD Program in Translational Medicine, Kaohsiung Medical University, Kaohsiung 80708, and Academia Sinica, Taipei 11529, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Department of Pediatrics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei 11529, TaiwanDepartment of Computer Science, National Yang Ming Chiao Tung University, Hsinchu 30093, TaiwanDepartment of Computer Science, National Yang Ming Chiao Tung University, Hsinchu 30093, TaiwanInstitute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Innovative Cellular Therapy Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, TaiwanPhD Program in Translational Medicine, Kaohsiung Medical University, Kaohsiung 80708, and Academia Sinica, Taipei 11529, Taiwan; Department of Pediatrics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Laboratory Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Translational Research Center of Neuromuscular Diseases, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30093, Taiwan; Corresponding author Yuh-Jyh Jong, Departments of Pediatrics and Laboratory Medicine, and Translational Research Center of Neuromuscular Diseases, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.PhD Program in Translational Medicine, Kaohsiung Medical University, Kaohsiung 80708, and Academia Sinica, Taipei 11529, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 11529, Taiwan; Corresponding author Jun-An Chen, Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by the selective loss of spinal motor neurons (MNs) and concomitant muscle weakness. Mutation of SMN1 is known to cause SMA, and restoring SMN protein levels via antisense oligonucleotide treatment is effective for ameliorating symptoms. However, this approach is hindered by exorbitant costs, invasive procedures, and poor treatment responses of some patients. Here, we seek to circumvent these hurdles by identifying reliable biomarkers that could predict treatment efficacy. We uncovered that MiR34 exhibits consistent downregulation during SMA progression in both human and rodent contexts. Importantly, Mir34 family-knockout mice display axon swelling and reduced neuromuscular junction (NMJ) endplates, recapitulating SMA pathology. Introducing MiR34a via scAAV9 improved the motor ability of SMNΔ7 mice, possibly by restoring NMJ endplate size. Finally, we observed a consistent decreasing trend in MiR34 family expression in the cerebrospinal fluid (CSF) of type I SMA patients during the loading phase of nusinersen treatment. Baseline CSF MiR34 levels before nusinersen injection proved predictive of patient motor skills 1 year later. Thus, we propose that MiR34 may serve as a biomarker of SMA since it is associated with the pathology and can help evaluate the therapeutic effects of nusinersen.http://www.sciencedirect.com/science/article/pii/S2162253123000641MT: Non-coding RNAsspinal muscular atrophySMAASOnusinersenmicroRNA |
| spellingShingle | Tai-Heng Chen Shih-Hsin Chang Yu-Fu Wu Ya-Ping Yen Fang-Yu Hsu Yen-Chung Chen Yang Ming Ho-Chiang Hsu Yi-Ching Su Sheng-Tang Wong Jui-Hung Hung Shih-Hwa Chiou Yuh-Jyh Jong Jun-An Chen MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice Molecular Therapy: Nucleic Acids MT: Non-coding RNAs spinal muscular atrophy SMA ASO nusinersen microRNA |
| title | MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice |
| title_full | MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice |
| title_fullStr | MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice |
| title_full_unstemmed | MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice |
| title_short | MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice |
| title_sort | mir34 contributes to spinal muscular atrophy and aav9 mediated delivery of mir34a ameliorates the motor deficits in sma mice |
| topic | MT: Non-coding RNAs spinal muscular atrophy SMA ASO nusinersen microRNA |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123000641 |
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