A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.
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DOI：
10.1016/j.stemcr.2017.01.011
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发表时间：
2017-03-14
影响因子：
5.9
通讯作者：
Schapira AHV
中科院分区：
文献类型：
--
作者：
Yang SY;Beavan M;Chau KY;Taanman JW;Schapira AHV
从数值上讲，帕金森病（PD）发展的最重要风险因素是葡萄糖脑苷脂酶GBA 1基因突变的存在。体外和体内研究表明，GBA 1突变降低了葡萄糖脑苷脂酶（GCase）活性，并与α-突触核蛋白水平升高相关，反映了在特发性PD脑中观察到的类似变化。我们已经开发了一种神经嵴干细胞衍生的多巴胺能神经元模型，该模型概括了GBA 1突变相关PD的生化异常。细胞显示GCase蛋白和活性降低，大自噬受损，α-突触核蛋白水平升高。这种方法的优点包括容易获得干细胞，不需要重新编程，并保留完整的宿主基因组。用GCase伴侣蛋白处理增加了GCase蛋白水平和活性，挽救了自噬缺陷，并降低了α-突触核蛋白水平。这些结果为进一步研究GCase分子伴侣或类似药物减缓PD进展提供了基础。神经元模型概括了GBA 1突变PD的生化异常氨溴索挽救了人GBA 1突变神经元细胞中的自噬缺陷氨溴索降低了人GBA 1突变神经元细胞中的α-突触核蛋白水平Schapira及其同事设计了一种来自人脂肪NCSC的多巴胺能神经元模型，该模型为葡萄糖脑苷脂酶功能障碍在PD发病机制中的作用提供了见解。葡萄糖脑苷脂酶功能增强逆转GBA 1突变神经元的生化异常。该方法提供了测试用于PD治疗的潜在治疗化合物的平台。
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD. A neuronal model recapitulates biochemical abnormalities in GBA1 mutation PD Ambroxol rescued the autophagic defects in human GBA1 mutant neuronal cells Ambroxol decreased α-synuclein levels human GBA1 mutant neuronal cells Schapira and colleagues devised a dopaminergic neuronal model from human adipose NCSCs which provided insights into the role of glucocerebrosidase dysfunction in PD pathogenesis. Glucocerebrosidase function enhancement reversed biochemical abnormalities in GBA1 mutant neurons. This method provides a platform to test potential therapeutic compounds for PD treatment.