Proteomic analysis of mouse models of Niemann-Pick C disease reveals alterations in the steady-state levels of lysosomal proteins within the brain.
Proteomic analysis of mouse models of Niemann-Pick C disease reveals alterations in the steady-state levels of lysosomal proteins within the brain.
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DOI：
10.1002/pmic.201200205
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发表时间：
2012-12
期刊：
影响因子：
3.4
通讯作者：
Lobel, Peter
中科院分区：
文献类型：
--
作者：
Sleat, David E.;Wiseman, Jennifer A.;Sohar, Istvan;El-Banna, Mukarram;Zheng, Haiyan;Moore, Dirk F.;Lobel, Peter
尼曼-皮克 C 病 (NPC) 是一种神经退行性溶酶体疾病，其特征是由于 NPC1（一种参与溶酶体胆固醇输出的跨膜蛋白）或 NPC2（一种溶酶体内胆固醇转运蛋白）缺陷引起的胆固醇和其他脂质储存。溶酶体活性的改变与 NPC 发病机制有关，因此本研究的目的是对 NPC1 或 NPC2 缺陷小鼠的溶酶体蛋白进行蛋白质组分析，以确定可能与疾病相关的继发性变化。从疾病进展不同阶段的野生型和 Npc1−/− 和 Npc2−/− 突变小鼠大脑中纯化含有特定甘露糖 6-磷酸修饰的溶酶体蛋白，并通过自下而上的 LC-MS/MS 进行鉴定，并通过光谱计数进行定量。在两种形式的 NPC 中，参与脂质分解代谢的许多溶酶体蛋白（包括 prosaposin 和 β-己糖胺酶的两个亚基）的水平均升高，可能代表细胞对鞘糖脂积累的补偿性反应。其他几种溶酶体蛋白也发生了显着改变，包括蛋白酶和糖苷酶。溶酶体蛋白水平的变化与活性和转录水平的类似变化相对应。了解这些变化的基本原理可能有助于深入了解鼻咽癌的病理生理学。
Niemann-Pick C disease (NPC) is a neurodegenerative lysosomal disorder characterized by storage of cholesterol and other lipids caused by defects in NPC1, a transmembrane protein involved in cholesterol export from the lysosome, or NPC2, an intralysosomal cholesterol transport protein. Alterations in lysosomal activities have been implicated in NPC pathogenesis therefore the aim of this study was to conduct a proteomic analysis of lysosomal proteins in mice deficient in either NPC1 or NPC2 to identify secondary changes that might be associated with disease. Lysosomal proteins containing the specific mannose 6-phosphate modification were purified from wild-type and Npc1−/− and Npc2−/− mutant mouse brains at different stages of disease progression and identified by bottom-up LC-MS/MS and quantified by spectral counting. Levels of a number of lysosomal proteins involved in lipid catabolism including prosaposin and the two subunits of β-hexosaminidase were increased in both forms of NPC, possibly representing a compensatory cellular response to the accumulation of glycosphingolipids. Several other lysosomal proteins were significantly altered, including proteases and glycosidases. Changes in lysosomal protein levels corresponded with similar alterations in activities and transcript levels. Understanding the rationale for such changes may provide insights into the pathophysiology of NPC.
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影响因子：
4.8
作者：
Infante, Rodney E.;Abi-Mosleh, Lina;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
3.8
作者：
Chikh, K;Vey, S;Millat, G
通讯作者：
Millat, G
影响因子：
4.8
作者：
Liou, Heng-Ling;Dixit, Sayali S.;Lobel, Peter
通讯作者：
Lobel, Peter
DOI：
10.1073/pnas.87.9.3493
发表时间：
1990-05-01
影响因子：
11.1
作者：
MORIMOTO, S;YAMAMOTO, Y;KISHIMOTO, Y
通讯作者：
KISHIMOTO, Y
影响因子：
4.4
作者：
Craig, R;Cortens, JP;Beavis, RC
通讯作者：
Beavis, RC