Section on Developmental Genetics, PEMG, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Nat Commun. 2017 Mar 7;8:14612. doi: 10.1038/ncomms14612.
Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1 mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1 mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases.
溶酶体酸化缺陷几乎与所有溶酶体贮积症（LSD）以及阿尔茨海默病和帕金森病等常见神经退行性疾病有关。尽管其具有重要意义，但该缺陷背后的机制尚不清楚。V-ATPase 是一种由胞质 V1 亚基和溶酶体膜锚定的 V0 亚基组成的多亚基蛋白复合物，调节溶酶体酸化。CLN1 基因编码 PPT1 的突变导致毁灭性的神经退行性 LSD，即 INCL。在这里，我们报告在模拟 INCL 的 Cln1 小鼠中，降低的 V-ATPase 活性与升高的溶酶体 pH 相关。此外，V0 亚基（V0a1）的 V-ATPase 亚基 a1 需要棕榈酰化才能分别与衔接蛋白-2（AP-2）和衔接蛋白-3（AP-3）相互作用，从而转运到溶酶体膜。值得注意的是，用硫酯酶（Ppt1）类似物 NtBuHA 治疗 Cln1 小鼠可改善这种缺陷。我们的发现揭示了 Cln1 调节 V0a1 溶酶体靶向的意外作用，并表明不同的因素对 V-ATPase 功能的不利影响会导致其他 LSD 和常见神经退行性疾病中的溶酶体酸化失调。
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