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SNX8 enables lysosome reformation and reverses lysosomal storage disorder

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  • Xinran Li

    (Zhejiang University
    Zhejiang University
    ZJU-Hangzhou Global Scientific and Technological Innovation Center
    Zhejiang University)

  • Cong Xiang

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Shilei Zhu

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Jiansheng Guo

    (Zhejiang University)

  • Chang Liu

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Ailian Wang

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Jin Cao

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Yan Lu

    (Zhejiang University
    Zhejiang University
    The Fourth Affiliated Hospital of Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Dante Neculai

    (The Fourth Affiliated Hospital of Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Pinglong Xu

    (Zhejiang University
    Zhejiang University
    ZJU-Hangzhou Global Scientific and Technological Innovation Center
    Zhejiang University)

  • Xin-Hua Feng

    (Zhejiang University
    Zhejiang University
    Zhejiang University
    Zhejiang University)

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.

Suggested Citation

  • Xinran Li & Cong Xiang & Shilei Zhu & Jiansheng Guo & Chang Liu & Ailian Wang & Jin Cao & Yan Lu & Dante Neculai & Pinglong Xu & Xin-Hua Feng, 2024. "SNX8 enables lysosome reformation and reverses lysosomal storage disorder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46705-x
    DOI: 10.1038/s41467-024-46705-x
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    References listed on IDEAS

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    1. Michela Palmieri & Rituraj Pal & Hemanth R. Nelvagal & Parisa Lotfi & Gary R. Stinnett & Michelle L. Seymour & Arindam Chaudhury & Lakshya Bajaj & Vitaliy V. Bondar & Laura Bremner & Usama Saleem & De, 2017. "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases," Nature Communications, Nature, vol. 8(1), pages 1-19, April.
    2. Li Yu & Christina K. McPhee & Lixin Zheng & Gonzalo A. Mardones & Yueguang Rong & Junya Peng & Na Mi & Ying Zhao & Zhihua Liu & Fengyi Wan & Dale W. Hailey & Viola Oorschot & Judith Klumperman & Eric , 2010. "Termination of autophagy and reformation of lysosomes regulated by mTOR," Nature, Nature, vol. 465(7300), pages 942-946, June.
    3. Michela Palmieri & Rituraj Pal & Hemanth R. Nelvagal & Parisa Lotfi & Gary R. Stinnett & Michelle L. Seymour & Arindam Chaudhury & Lakshya Bajaj & Vitaliy V. Bondar & Laura Bremner & Usama Saleem & De, 2017. "Correction: Corrigendum: mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases," Nature Communications, Nature, vol. 8(1), pages 1-3, August.
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