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.

溶酶体储存障碍（LSD）具有常见的表型，包括溶酶体增大和溶酶体储存缺陷，是由溶酶体相关基因突变引起的。尽管已经探索了基因疗法和酶替代疗法，但目前还没有针对 LSD 的有效常规疗法。在溶酶体重组过程中，当功能性溶酶体池减少时，溶酶体脂质和蛋白质被回收以恢复溶酶体功能。在这里，我们报道分选连接蛋白 SNX8 促进溶酶体管状形成，这是溶酶体重组所需的过程，并且 SNX8 的缺失会导致人类细胞中 LSD 的表型特征。 SNX8 过表达挽救了细胞中 LSD 的特征，而基于 AAV 的 SNX8 向大脑的递送则挽救了小鼠的 LSD 表型。重要的是，通过筛选天然化合物库，我们鉴定了三种小分子，它们可以增强 SNX8-溶酶体结合并逆转人类细胞和小鼠中的 LSD 表型。总而言之，我们的结果为 LSD 的治疗提供了潜在的解决方案。