Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models
Abstract Glaucoma is a group of diseases that leads to chronic degeneration of retinal ganglion cell (RGC) axons and progressive loss of RGCs, resulting in vision loss. While aging and elevated intraocular pressure (IOP) have been identified as the main contributing factors to glaucoma, the molecula...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06086-3 |
| _version_ | 1797682578583453696 |
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| author | Angela Dixon Myoung Sup Shim April Nettesheim Aislyn Coyne Chien-Chia Su Haiyan Gong Paloma B. Liton |
| author_facet | Angela Dixon Myoung Sup Shim April Nettesheim Aislyn Coyne Chien-Chia Su Haiyan Gong Paloma B. Liton |
| author_sort | Angela Dixon |
| collection | DOAJ |
| description | Abstract Glaucoma is a group of diseases that leads to chronic degeneration of retinal ganglion cell (RGC) axons and progressive loss of RGCs, resulting in vision loss. While aging and elevated intraocular pressure (IOP) have been identified as the main contributing factors to glaucoma, the molecular mechanisms and signaling pathways triggering RGC death and axonal degeneration are not fully understood. Previous studies in our laboratory found that overactivation of autophagy in DBA/2J::GFP-LC3 mice led to RGC death and optic nerve degeneration with glaucomatous IOP elevation. We found similar findings in aging GFP-LC3 mice subjected to chronic IOP elevation. Here, we further investigated the impact of autophagy deficiency on autophagy-deficient DBA/2J-Atg4b ko and DBA/2J-Atg4b +/− mice, generated in our laboratory via CRISPR/Cas9 technology; as well as in Atg4b ko mice subjected to the experimental TGFβ2 chronic ocular hypertensive model. Our data shows that, in contrast to DBA/2J and DBA/2J-Atg4b +/− littermates, DBA/2J-Atg4b ko mice do not develop glaucomatous IOP elevation. Atg4b deficiency also protected against glaucomatous IOP elevation in the experimental TGFβ2 chronic ocular hypertensive model. Atg4 deletion did not compromise RGC or optic nerve survival in Atg4b ko mice. Moreover, our results indicate a protective role of autophagy deficiency against RGC death and ON atrophy in the hypertensive DBA/2J-Atg4b +/− mice. Together, our data suggests a pathogenic role of autophagy activation in ocular hypertension and glaucoma. |
| first_indexed | 2024-03-12T00:01:47Z |
| format | Article |
| id | doaj.art-1844fe9532ee42fba89bf6ef50cd893c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T00:01:47Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-1844fe9532ee42fba89bf6ef50cd893c2023-09-17T11:29:20ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811110.1038/s41419-023-06086-3Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse modelsAngela Dixon0Myoung Sup Shim1April Nettesheim2Aislyn Coyne3Chien-Chia Su4Haiyan Gong5Paloma B. Liton6Department of Ophthalmology & Pathology, Duke UniversityDepartment of Ophthalmology & Pathology, Duke UniversityDepartment of Ophthalmology & Pathology, Duke UniversityDepartment of Ophthalmology & Pathology, Duke UniversityDepartment of Ophthalmology & Pathology, Duke UniversityDepartment of Ophthalmology, Boston University School of MedicineDepartment of Ophthalmology & Pathology, Duke UniversityAbstract Glaucoma is a group of diseases that leads to chronic degeneration of retinal ganglion cell (RGC) axons and progressive loss of RGCs, resulting in vision loss. While aging and elevated intraocular pressure (IOP) have been identified as the main contributing factors to glaucoma, the molecular mechanisms and signaling pathways triggering RGC death and axonal degeneration are not fully understood. Previous studies in our laboratory found that overactivation of autophagy in DBA/2J::GFP-LC3 mice led to RGC death and optic nerve degeneration with glaucomatous IOP elevation. We found similar findings in aging GFP-LC3 mice subjected to chronic IOP elevation. Here, we further investigated the impact of autophagy deficiency on autophagy-deficient DBA/2J-Atg4b ko and DBA/2J-Atg4b +/− mice, generated in our laboratory via CRISPR/Cas9 technology; as well as in Atg4b ko mice subjected to the experimental TGFβ2 chronic ocular hypertensive model. Our data shows that, in contrast to DBA/2J and DBA/2J-Atg4b +/− littermates, DBA/2J-Atg4b ko mice do not develop glaucomatous IOP elevation. Atg4b deficiency also protected against glaucomatous IOP elevation in the experimental TGFβ2 chronic ocular hypertensive model. Atg4 deletion did not compromise RGC or optic nerve survival in Atg4b ko mice. Moreover, our results indicate a protective role of autophagy deficiency against RGC death and ON atrophy in the hypertensive DBA/2J-Atg4b +/− mice. Together, our data suggests a pathogenic role of autophagy activation in ocular hypertension and glaucoma.https://doi.org/10.1038/s41419-023-06086-3 |
| spellingShingle | Angela Dixon Myoung Sup Shim April Nettesheim Aislyn Coyne Chien-Chia Su Haiyan Gong Paloma B. Liton Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models Cell Death and Disease |
| title | Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| title_full | Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| title_fullStr | Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| title_full_unstemmed | Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| title_short | Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| title_sort | autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontaneous glaucoma mouse models |
| url | https://doi.org/10.1038/s41419-023-06086-3 |
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