E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration
Abstract Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of id...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-53731-8 |
| _version_ | 1797275158172401664 |
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| author | Yeshumenesh Zegeye Bogale Aredo Seher Yuksel Dogan Can Kirman Ashwani Kumar Bo Chen Emily Turpin Sangita Shresta Yu-Guang He Laurent Gautron Miao Tang Xiaohong Li Sophia M. DiCesare John D. Hulleman Chao Xing Sara Ludwig Eva Marie Y. Moresco Bruce A. Beutler Rafael L. Ufret-Vincenty |
| author_facet | Yeshumenesh Zegeye Bogale Aredo Seher Yuksel Dogan Can Kirman Ashwani Kumar Bo Chen Emily Turpin Sangita Shresta Yu-Guang He Laurent Gautron Miao Tang Xiaohong Li Sophia M. DiCesare John D. Hulleman Chao Xing Sara Ludwig Eva Marie Y. Moresco Bruce A. Beutler Rafael L. Ufret-Vincenty |
| author_sort | Yeshumenesh Zegeye |
| collection | DOAJ |
| description | Abstract Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3 -/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin–proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study. |
| first_indexed | 2024-03-07T15:10:16Z |
| format | Article |
| id | doaj.art-9429c796dd824374af717a5bef932a51 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:10:16Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9429c796dd824374af717a5bef932a512024-03-05T18:42:35ZengNature PortfolioScientific Reports2045-23222024-02-0114111810.1038/s41598-024-53731-8E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegenerationYeshumenesh Zegeye0Bogale Aredo1Seher Yuksel2Dogan Can Kirman3Ashwani Kumar4Bo Chen5Emily Turpin6Sangita Shresta7Yu-Guang He8Laurent Gautron9Miao Tang10Xiaohong Li11Sophia M. DiCesare12John D. Hulleman13Chao Xing14Sara Ludwig15Eva Marie Y. Moresco16Bruce A. Beutler17Rafael L. Ufret-Vincenty18Department of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterMcDermott Center for Human Growth and Development, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterCenter for Hypothalamic Research and Department of Internal Medicine, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterMcDermott Center for Human Growth and Development, UT Southwestern Medical CenterCenter for Hypothalamic Research and Department of Internal Medicine, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterDepartment of Ophthalmology, UT Southwestern Medical CenterAbstract Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3 -/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin–proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study.https://doi.org/10.1038/s41598-024-53731-8Herc3Forward geneticsENU-mutagenesisCRISPRRetinal neurodegenerationFundus spots |
| spellingShingle | Yeshumenesh Zegeye Bogale Aredo Seher Yuksel Dogan Can Kirman Ashwani Kumar Bo Chen Emily Turpin Sangita Shresta Yu-Guang He Laurent Gautron Miao Tang Xiaohong Li Sophia M. DiCesare John D. Hulleman Chao Xing Sara Ludwig Eva Marie Y. Moresco Bruce A. Beutler Rafael L. Ufret-Vincenty E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration Scientific Reports Herc3 Forward genetics ENU-mutagenesis CRISPR Retinal neurodegeneration Fundus spots |
| title | E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| title_full | E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| title_fullStr | E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| title_full_unstemmed | E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| title_short | E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| title_sort | e3 ubiquitin ligase herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration |
| topic | Herc3 Forward genetics ENU-mutagenesis CRISPR Retinal neurodegeneration Fundus spots |
| url | https://doi.org/10.1038/s41598-024-53731-8 |
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