Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.
Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.
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DOI：
10.1371/journal.pone.0006951
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发表时间：
2009-09-11
期刊：
影响因子：
3.7
通讯作者：
Walkley SU
中科院分区：
文献类型：
--
作者：
Davidson CD;Ali NF;Micsenyi MC;Stephney G;Renault S;Dobrenis K;Ory DS;Vanier MT;Walkley SU
C 型尼曼-匹克 (NPC) 病是一种致命的神经退行性疾病，最常见的是由 NPC1 蛋白缺陷引起，其特征是细胞内广泛积累未酯化胆固醇和鞘糖脂 (GSL)。虽然目前的治疗方法有限，但在 Npc1−/− 小鼠中测试的一些药物已显示出部分疗效。在使用两种此类化合物 N-丁基脱氧野尻霉素 (NB-DNJ) 和四氢孕酮的联合治疗试验中，我们注意到仅接受四氢孕酮载体 2-羟丙基-β-环糊精 (CD) 的 Npc1−/− 小鼠的寿命增加。这一发现表明，单独给予 CD，但频率更高，可能会带来额外的益处。从 P7 或 P21 开始对 Npc1−/− 小鼠进行 CD 给药，每隔一天持续一次，可延迟临床发作，减少神经元内胆固醇和 GSL 储存以及游离鞘氨醇积累，减少神经变性标志物，并导致比任何先前治疗方案更长的生存期。我们推断，以胆固醇和 GSL 积累为特征的其他溶酶体疾病，包括 NPC2 缺陷导致的 NPC 疾病、GM1 神经节苷脂贮积症和 IIIA 型粘多糖贮积症 (MPS)，同样可能受益于 CD 治疗。接受治疗的 Npc2−/− 小鼠表现出与 NPC1 疾病相似的益处，然而，患有 GM1 神经节苷脂沉积症或 MPS IIIA 的小鼠未能表现出储存量减少。 CD治疗延迟了Npc1−/−和Npc2−/−小鼠的临床疾病发作，减少了神经元内储存和神经变性的次要标志物，并显着延长了寿命。相比之下，CD 未能改善 GM1 神经节苷脂沉积症和 MPS IIIA 疾病中的胆固醇或鞘糖脂储存。了解 CD 导致神经元储存减少的机制可能为治疗 NPC 和以胆固醇稳态失调为特征的相关神经退行性疾病提供重要的新机会。
Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1−/− mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1−/− mice receiving only 2-hydroxypropyl-β-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. Administration of CD to Npc1−/− mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2−/− mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1−/− and Npc2−/− mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.
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