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Quantitative Proteomic Analysis of Niemann-Pick Disease Type C1 Cerebellum Identifies Protein Biomarkers and Provides Pathological Insight

机译：尼曼匹克病C1型小脑标识蛋白质生物标记定量蛋白质组学分析并提供洞察病理

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Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.
机译：N1型尼曼-匹克病（Niemann-Pick disease，NPC1）是一种致命的神经退行性疾病，目前尚无明确的治疗方法。在NPC1中，包括神经发炎，氧化应激和神经元凋亡在内的病理级联反应可能与临床表型有关。虽然NPC1的遗传原因是已知的，但我们试图通过鉴定Npc1突变型小鼠小脑中差异表达的蛋白质来进一步了解病理生理学。使用二维凝胶电泳和质谱，与对照组相比，在Npc1突变型小鼠小脑中鉴定出77种差异表达的蛋白质。这些包括与葡萄糖代谢，排毒/氧化应激有关的蛋白质和与阿尔茨海默氏病相关的蛋白质。此外，发现脂肪酸结合蛋白家族的成员，包括FABP3，FABP5和FABP7，相对于对照在Npc1突变型小脑中具有改变的表达。将我们从鼠类模型中获得的结果转化为患者，我们确认相对于儿科对照，NPC1患者脑脊液中谷胱甘肽S-转移酶α，超氧化物歧化酶和FABP3的表达发生了改变。与未接受米格司他治疗的患者相比，接受米格司他（一种糖鞘脂合成抑制剂）的NPC1患者亚组显示出FABP3水平显着降低。这项研究提供了NPC1中蛋白质失调的初步报告，这将有助于NPC1病理的进一步研究并促进治疗性试验的实施。

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