Department of Biochemistry, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany.
Department of Paediatrics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Int J Mol Sci. 2024 Oct 22;25(21):11361. doi: 10.3390/ijms252111361.
Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder where 95% of the cases are caused by mutations in the Niemann-Pick C1 (NPC1) gene. Loss of function in NPC1 mutants trigger the accumulation of cholesterol in late endo-lysosomes and lysosomal dysfunction. The current study examined the potential of polyphenol-rich methanol extracts from L. (RCME) and two of its components, rutin and quercitrin, to enhance protein trafficking of NPC1 and restore cholesterol levels in fibroblasts derived from NPC patients, in comparison with miglustat, a drug approved in Europe for NPC treatment. Interestingly, RCME improved the trafficking of the compound heterozygous mutant NPC1, homozygous mutant NPC1, and heterozygous mutant NPC1 between the endoplasmic reticulum and the Golgi and significantly reduced the levels of cellular cholesterol in the cell lines examined. Miglustat did not affect the trafficking of the three NPC1 mutants individually nor in combination with RCME. Markedly, rutin and quercitrin exerted their effects on cholesterol, but not in the trafficking pathway of NPC1, indicating that other components in RCME are implicated in regulating the trafficking of NPC1 mutants. By virtue of its dual function in targeting the trafficking of mutants of NPC1 as well as the cholesterol contents, RCME is more beneficial than available drugs that target substrate reduction and should be therefore considered in further studies for its feasibility as a therapeutic agent for NPC patients.
尼曼-匹克 C 型（NPC）疾病是一种常染色体隐性溶酶体贮积症，其中 95%的病例是由尼曼-匹克 C1（NPC1）基因突变引起的。NPC1 突变体的功能丧失会触发胆固醇在晚期内体-溶酶体中的积累和溶酶体功能障碍。本研究考察了富含多酚的甲醇提取物（RCME）及其两种成分芦丁和槲皮素，与已在欧洲批准用于 NPC 治疗的药物米格列醇相比，在增强 NPC1 蛋白转运和恢复 NPC 患者成纤维细胞胆固醇水平方面的潜力。有趣的是，RCME 改善了复合杂合突变 NPC1、纯合突变 NPC1 和 NPC1 杂合突变在 ER 和高尔基体之间的转运，并显著降低了所研究细胞系中的细胞胆固醇水平。米格列醇单独或与 RCME 联合使用均不影响三种 NPC1 突变体的转运。值得注意的是，芦丁和槲皮素对胆固醇有影响，但对 NPC1 的转运途径没有影响，这表明 RCME 中的其他成分参与调节 NPC1 突变体的转运。由于其在靶向 NPC1 突变体的转运以及胆固醇含量方面的双重作用，RCME 比针对底物减少的现有药物更有益，因此应在进一步的研究中考虑其作为 NPC 患者治疗剂的可行性。
