DLK-dependent axonal mitochondrial fission drives degeneration after axotomy
Abstract Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal c...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54982-9 |
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| author | Jorge Gómez-Deza Matthew Nebiyou Mor R. Alkaslasi Francisco M. Nadal-Nicolás Preethi Somasundaram Anastasia L. Slavutsky Wei Li Michael E. Ward Trent A. Watkins Claire E. Le Pichon |
| author_facet | Jorge Gómez-Deza Matthew Nebiyou Mor R. Alkaslasi Francisco M. Nadal-Nicolás Preethi Somasundaram Anastasia L. Slavutsky Wei Li Michael E. Ward Trent A. Watkins Claire E. Le Pichon |
| author_sort | Jorge Gómez-Deza |
| collection | DOAJ |
| description | Abstract Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention. |
| format | Article |
| id | doaj-art-b0cab9e2cc844f6784df5d9da746375f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b0cab9e2cc844f6784df5d9da746375f2025-01-05T12:34:44ZengNature PortfolioNature Communications2041-17232024-12-0115111810.1038/s41467-024-54982-9DLK-dependent axonal mitochondrial fission drives degeneration after axotomyJorge Gómez-Deza0Matthew Nebiyou1Mor R. Alkaslasi2Francisco M. Nadal-Nicolás3Preethi Somasundaram4Anastasia L. Slavutsky5Wei Li6Michael E. Ward7Trent A. Watkins8Claire E. Le Pichon9Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthNational Eye Institute, National Institutes of HealthDepartment of Neurosurgery, Baylor College of MedicineEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthNational Eye Institute, National Institutes of HealthNational Institute of Neurological Disorders and Stroke, National Institutes of HealthDepartment of Neurosurgery, Baylor College of MedicineEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthAbstract Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.https://doi.org/10.1038/s41467-024-54982-9 |
| spellingShingle | Jorge Gómez-Deza Matthew Nebiyou Mor R. Alkaslasi Francisco M. Nadal-Nicolás Preethi Somasundaram Anastasia L. Slavutsky Wei Li Michael E. Ward Trent A. Watkins Claire E. Le Pichon DLK-dependent axonal mitochondrial fission drives degeneration after axotomy Nature Communications |
| title | DLK-dependent axonal mitochondrial fission drives degeneration after axotomy |
| title_full | DLK-dependent axonal mitochondrial fission drives degeneration after axotomy |
| title_fullStr | DLK-dependent axonal mitochondrial fission drives degeneration after axotomy |
| title_full_unstemmed | DLK-dependent axonal mitochondrial fission drives degeneration after axotomy |
| title_short | DLK-dependent axonal mitochondrial fission drives degeneration after axotomy |
| title_sort | dlk dependent axonal mitochondrial fission drives degeneration after axotomy |
| url | https://doi.org/10.1038/s41467-024-54982-9 |
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