SNX8 enables lysosome reformation and reverses lysosomal storage disorder

Xinran Li, Cong Xiang, Shilei Zhu, Jiansheng Guo, Chang Liu, Ailian Wang, Jin Cao, Yan Lu, Dante Neculai, Pinglong Xu and Xin-Hua Feng ()
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Xinran Li: Zhejiang University
Cong Xiang: Zhejiang University
Shilei Zhu: Zhejiang University
Jiansheng Guo: Zhejiang University
Chang Liu: Zhejiang University
Ailian Wang: Zhejiang University
Jin Cao: Zhejiang University
Yan Lu: Zhejiang University
Dante Neculai: The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Pinglong Xu: Zhejiang University
Xin-Hua Feng: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46705-x

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