Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans
Abstract Background Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncert...
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| Format: | Article |
| Language: | English |
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BMC
2025-04-01
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| Series: | Translational Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s40035-025-00480-x |
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| author | Kyung Hwan Park Euihyeon Yu Sooji Choi Sangyeong Kim Chanbin Park J. Eugene Lee Kyung Won Kim |
| author_facet | Kyung Hwan Park Euihyeon Yu Sooji Choi Sangyeong Kim Chanbin Park J. Eugene Lee Kyung Won Kim |
| author_sort | Kyung Hwan Park |
| collection | DOAJ |
| description | Abstract Background Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it. Methods To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly. Results We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans. Conclusions We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy. |
| format | Article |
| id | doaj-art-e08c67ddecce4eaeb596c51b55e22c4e |
| institution | OA Journals |
| issn | 2047-9158 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj-art-e08c67ddecce4eaeb596c51b55e22c4e2025-08-20T02:28:11ZengBMCTranslational Neurodegeneration2047-91582025-04-0114111610.1186/s40035-025-00480-xOptogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegansKyung Hwan Park0Euihyeon Yu1Sooji Choi2Sangyeong Kim3Chanbin Park4J. Eugene Lee5Kyung Won Kim6Department of Life Science, Multidisciplinary Genome Institute, Hallym UniversityDepartment of Life Science, Multidisciplinary Genome Institute, Hallym UniversityDepartment of Life Science, Multidisciplinary Genome Institute, Hallym UniversityDepartment of Life Science, Multidisciplinary Genome Institute, Hallym UniversityBiometrology Group, Division of Biomedical Metrology, Korea Research Institute of Standards and ScienceBiometrology Group, Division of Biomedical Metrology, Korea Research Institute of Standards and ScienceDepartment of Life Science, Multidisciplinary Genome Institute, Hallym UniversityAbstract Background Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it. Methods To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly. Results We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans. Conclusions We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.https://doi.org/10.1186/s40035-025-00480-xNeurodegenerative diseasesOptogeneticsOptoDropletTDP-43 proteinopathyAmyotrophic lateral sclerosisFrontotemporal lobar degeneration |
| spellingShingle | Kyung Hwan Park Euihyeon Yu Sooji Choi Sangyeong Kim Chanbin Park J. Eugene Lee Kyung Won Kim Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans Translational Neurodegeneration Neurodegenerative diseases Optogenetics OptoDroplet TDP-43 proteinopathy Amyotrophic lateral sclerosis Frontotemporal lobar degeneration |
| title | Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans |
| title_full | Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans |
| title_fullStr | Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans |
| title_full_unstemmed | Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans |
| title_short | Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans |
| title_sort | optogenetic induction of tdp 43 aggregation impairs neuronal integrity and behavior in caenorhabditis elegans |
| topic | Neurodegenerative diseases Optogenetics OptoDroplet TDP-43 proteinopathy Amyotrophic lateral sclerosis Frontotemporal lobar degeneration |
| url | https://doi.org/10.1186/s40035-025-00480-x |
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