Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders
Abstract Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicabl...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59165-8 |
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| author | Fay Newton Mihail Halachev Linda Nguyen Lisa McKie Pleasantine Mill Roly Megaw |
| author_facet | Fay Newton Mihail Halachev Linda Nguyen Lisa McKie Pleasantine Mill Roly Megaw |
| author_sort | Fay Newton |
| collection | DOAJ |
| description | Abstract Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients. |
| format | Article |
| id | doaj-art-86508e881e6b4c269707dec8ca7acedd |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-86508e881e6b4c269707dec8ca7acedd2025-08-20T02:11:22ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-59165-8Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disordersFay Newton0Mihail Halachev1Linda Nguyen2Lisa McKie3Pleasantine Mill4Roly Megaw5MRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghMRC Human Genetics Unit, Institute of Genetics and Cancer, University of EdinburghAbstract Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.https://doi.org/10.1038/s41467-025-59165-8 |
| spellingShingle | Fay Newton Mihail Halachev Linda Nguyen Lisa McKie Pleasantine Mill Roly Megaw Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders Nature Communications |
| title | Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| title_full | Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| title_fullStr | Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| title_full_unstemmed | Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| title_short | Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| title_sort | autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders |
| url | https://doi.org/10.1038/s41467-025-59165-8 |
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