FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons
MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/173808 |
| _version_ | 1811677100387598336 |
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| author | Ho, Wan Yun Chak, Li-Ling Hor, Jin-Hui Liu, Fujia Diaz-Garcia, Sandra Chang, Jer-Cherng Sanford, Emma Rodriguez, Maria J. Alagappan, Durgadevi Lim, Su Min Cho, Yik-Lam Shimizu, Yuji Sun, Alfred Xuyang Tyan, Sheue-Houy Koo, Edward Kim, Seung Hyun Ravits, John Ng, Shi-Yan Okamura, Katsutomo Ling, Shuo-Chien |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Ho, Wan Yun Chak, Li-Ling Hor, Jin-Hui Liu, Fujia Diaz-Garcia, Sandra Chang, Jer-Cherng Sanford, Emma Rodriguez, Maria J. Alagappan, Durgadevi Lim, Su Min Cho, Yik-Lam Shimizu, Yuji Sun, Alfred Xuyang Tyan, Sheue-Houy Koo, Edward Kim, Seung Hyun Ravits, John Ng, Shi-Yan Okamura, Katsutomo Ling, Shuo-Chien |
| author_sort | Ho, Wan Yun |
| collection | NTU |
| description | MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS. |
| first_indexed | 2024-10-01T02:32:00Z |
| format | Journal Article |
| id | ntu-10356/173808 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:32:00Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1738082024-03-04T15:32:04Z FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons Ho, Wan Yun Chak, Li-Ling Hor, Jin-Hui Liu, Fujia Diaz-Garcia, Sandra Chang, Jer-Cherng Sanford, Emma Rodriguez, Maria J. Alagappan, Durgadevi Lim, Su Min Cho, Yik-Lam Shimizu, Yuji Sun, Alfred Xuyang Tyan, Sheue-Houy Koo, Edward Kim, Seung Hyun Ravits, John Ng, Shi-Yan Okamura, Katsutomo Ling, Shuo-Chien School of Biological Sciences Temasek Lifesciences Laboratory Medicine, Health and Life Sciences Cellular neuroscience Natural sciences MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS. Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by grants to S.Ng and K.O from the National Research Foundation, Singapore, to S.H.K from National Research Foundation (NRF) funded by the Ministry of Science, Korea (NRF-2018M3C7A1056512), to S.-C.L from the Swee LiewWadsworth Endowment fund, National University of Singapore (NUS), National Medical Research Council (NMRC/OFIRG/0042/2017), Singapore, Ministry of Education (MOE-T2EP30220-0014), Singapore, and National Research Foundation (NRF-ISF003-3221), Singapore. 2024-02-28T05:49:55Z 2024-02-28T05:49:55Z 2023 Journal Article Ho, W. Y., Chak, L., Hor, J., Liu, F., Diaz-Garcia, S., Chang, J., Sanford, E., Rodriguez, M. J., Alagappan, D., Lim, S. M., Cho, Y., Shimizu, Y., Sun, A. X., Tyan, S., Koo, E., Kim, S. H., Ravits, J., Ng, S., Okamura, K. & Ling, S. (2023). FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons. IScience, 26(11), 108152-. https://dx.doi.org/10.1016/j.isci.2023.108152 2589-0042 https://hdl.handle.net/10356/173808 10.1016/j.isci.2023.108152 37920668 2-s2.0-85174454412 11 26 108152 en NMRC/OFIRG/0042/2017 NRF-ISF003-3221 MOE-T2EP30220-0014 iScience © 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Cellular neuroscience Natural sciences Ho, Wan Yun Chak, Li-Ling Hor, Jin-Hui Liu, Fujia Diaz-Garcia, Sandra Chang, Jer-Cherng Sanford, Emma Rodriguez, Maria J. Alagappan, Durgadevi Lim, Su Min Cho, Yik-Lam Shimizu, Yuji Sun, Alfred Xuyang Tyan, Sheue-Houy Koo, Edward Kim, Seung Hyun Ravits, John Ng, Shi-Yan Okamura, Katsutomo Ling, Shuo-Chien FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title | FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title_full | FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title_fullStr | FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title_full_unstemmed | FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title_short | FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons |
| title_sort | fus dependent microrna deregulations identify trib2 as a druggable target for als motor neurons |
| topic | Medicine, Health and Life Sciences Cellular neuroscience Natural sciences |
| url | https://hdl.handle.net/10356/173808 |
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