SNX8 enables lysosome reformation and reverses lysosomal storage disorder
Abstract Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective r...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46705-x |
| _version_ | 1797247217239588864 |
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| author | Xinran Li Cong Xiang Shilei Zhu Jiansheng Guo Chang Liu Ailian Wang Jin Cao Yan Lu Dante Neculai Pinglong Xu Xin-Hua Feng |
| author_facet | Xinran Li Cong Xiang Shilei Zhu Jiansheng Guo Chang Liu Ailian Wang Jin Cao Yan Lu Dante Neculai Pinglong Xu Xin-Hua Feng |
| author_sort | Xinran Li |
| collection | DOAJ |
| description | Abstract Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective routine therapies against LSDs. During lysosome reformation, which occurs when the functional lysosome pool is reduced, lysosomal lipids and proteins are recycled to restore lysosome functions. Here we report that the sorting nexin protein SNX8 promotes lysosome tubulation, a process that is required for lysosome reformation, and that loss of SNX8 leads to phenotypes characteristic of LSDs in human cells. SNX8 overexpression rescued features of LSDs in cells, and AAV-based delivery of SNX8 to the brain rescued LSD phenotypes in mice. Importantly, by screening a natural compound library, we identified three small molecules that enhanced SNX8–lysosome binding and reversed LSD phenotypes in human cells and in mice. Altogether, our results provide a potential solution for the treatment of LSDs. |
| first_indexed | 2024-04-24T19:55:11Z |
| format | Article |
| id | doaj.art-a1738fc17a174dfaa7178f18c93ad607 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:55:11Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a1738fc17a174dfaa7178f18c93ad6072024-03-24T12:25:19ZengNature PortfolioNature Communications2041-17232024-03-0115111510.1038/s41467-024-46705-xSNX8 enables lysosome reformation and reverses lysosomal storage disorderXinran Li0Cong Xiang1Shilei Zhu2Jiansheng Guo3Chang Liu4Ailian Wang5Jin Cao6Yan Lu7Dante Neculai8Pinglong Xu9Xin-Hua Feng10The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityCenter of Cryo-Electron Microscopy, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityInternational Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of MedicineThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityAbstract Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective routine therapies against LSDs. During lysosome reformation, which occurs when the functional lysosome pool is reduced, lysosomal lipids and proteins are recycled to restore lysosome functions. Here we report that the sorting nexin protein SNX8 promotes lysosome tubulation, a process that is required for lysosome reformation, and that loss of SNX8 leads to phenotypes characteristic of LSDs in human cells. SNX8 overexpression rescued features of LSDs in cells, and AAV-based delivery of SNX8 to the brain rescued LSD phenotypes in mice. Importantly, by screening a natural compound library, we identified three small molecules that enhanced SNX8–lysosome binding and reversed LSD phenotypes in human cells and in mice. Altogether, our results provide a potential solution for the treatment of LSDs.https://doi.org/10.1038/s41467-024-46705-x |
| spellingShingle | Xinran Li Cong Xiang Shilei Zhu Jiansheng Guo Chang Liu Ailian Wang Jin Cao Yan Lu Dante Neculai Pinglong Xu Xin-Hua Feng SNX8 enables lysosome reformation and reverses lysosomal storage disorder Nature Communications |
| title | SNX8 enables lysosome reformation and reverses lysosomal storage disorder |
| title_full | SNX8 enables lysosome reformation and reverses lysosomal storage disorder |
| title_fullStr | SNX8 enables lysosome reformation and reverses lysosomal storage disorder |
| title_full_unstemmed | SNX8 enables lysosome reformation and reverses lysosomal storage disorder |
| title_short | SNX8 enables lysosome reformation and reverses lysosomal storage disorder |
| title_sort | snx8 enables lysosome reformation and reverses lysosomal storage disorder |
| url | https://doi.org/10.1038/s41467-024-46705-x |
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