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HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.
Journal of Lipid Research ( IF 6.5 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.jlr.2021.100114
Nina H Pipalia 1 , Syed Z Saad 1 , Kanagaraj Subramanian 2 , Abigail Cross 3 , Aisha Al-Motawa 1 , Kunal Garg 1 , Brian S J Blagg 4 , Len Neckers 5 , Paul Helquist 4 , Olaf Wiest 4 , Daniel S Ory 2 , Frederick R Maxfield 1
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Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.

中文翻译:

HSP90 抑制剂可减少 Niemann-Pick C1 型突变成纤维细胞中的胆固醇储存。

Niemann Pick C1 型 (NPC1) 病是一种由 NPC1 基因突变引起的溶酶体脂质贮积症。据报道,患者中存在 300 多种与疾病相关的突变,导致许多细胞类型的晚期内体和溶酶体 (LE/Ly) 中未酯化胆固醇、鞘糖脂和其他脂质的异常积累。以前,我们发现用组蛋白去乙酰化酶抑制剂处理许多不同的 NPC1 突变成纤维细胞会导致胆固醇储存减少,我们发现这与 NPC1 蛋白从内质网的排出和向 LE/Ly 的释放增强有关。这表明组蛋白去乙酰化酶抑制剂可能通过蛋白质伴侣的变化来增强 NPC1 突变体的折叠,使它们能够被传递到 LE/Ly。I1061T皮肤成纤维细胞。我们发现 HSP90 抑制导致胆固醇从 LE/Ly 中清除,这与突变 NPC1 I1061T蛋白向 LE/Ly 的传递增强有关。我们还观察到 HSP90 的抑制增加了 HSP70 的表达,而 HSP70 的过表达也减少了 NPC1 I1061T成纤维细胞中胆固醇的储存。然而,我们没有看到arimoclomol对胆固醇储存的校正,一种据报道增加HSP70表达的药物,剂量高达0.5 mM。这些结果表明,分子伴侣的操作可能会导致 NPC1 疾病的有效治疗,但需要进一步研究机制。
更新日期:2021-09-02
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