Glucocerebrosidase activity, cathepsin D and monomeric a-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.
Glucocerebrosidase activity, cathepsin D and monomeric a-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.
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PD 相关 GBA1 突变的干细胞衍生神经元模型中葡萄糖脑苷脂酶活性、组织蛋白酶 D 和单体 α-突触核蛋白相互作用。
DOI：
10.1016/j.nbd.2019.104620
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发表时间：
2020
影响因子：
6.1
通讯作者：
Yang SY
中科院分区：
文献类型：
--
作者：
Yang SY
GBA 1基因突变的存在增加了帕金森病（PD）的风险，但GBA 1相关PD的致病机制尚不清楚。鉴于受损的α-突触核蛋白转换是PD发病机制的标志，并且组织蛋白酶D是参与神经元细胞中α-突触核蛋白降解的关键酶，我们已经检查了人神经嵴干细胞衍生的多巴胺能神经元中葡萄糖脑苷脂酶（GCase）、组织蛋白酶D和单体α-突触核蛋白的关系。我们发现GCase的正常活性是组织蛋白酶D发挥其从神经元中去除单体α-突触核蛋白的功能所必需的。GBA 1突变导致神经元中组织蛋白酶D蛋白和活性水平降低，而单体α-突触核蛋白水平升高。当GBA 1突变神经元用GCase替代或伴侣治疗时，组织蛋白酶D蛋白水平和活性恢复，单体α-突触核蛋白减少。当组织蛋白酶D被抑制时，GCase替代不能降低GBA 1突变神经元中单体α-突触核蛋白的水平。这些数据表明，GBA 1基因突变通过影响神经元中的溶酶体组织蛋白酶D来增加单体α-突触核蛋白水平。
The presence ofGBA1gene mutations increases risk for Parkinson's disease (PD), but the pathogenic mechanisms ofGBA1associated PD remain unknown. Given that impaired α-synuclein turnover is a hallmark of PD pathogenesis and cathepsin D is a key enzyme involved in α-synuclein degradation in neuronal cells, we have examined the relationship of glucocerebrosidase (GCase), cathepsin D and monomeric α-synuclein in human neural crest stem cell derived dopaminergic neurons. We found that normal activity of GCase is necessary for cathepsin D to perform its function of monomeric α-synuclein removal from neurons.GBA1mutations lead to a lower level of cathepsin D protein and activity, and higher level of monomeric α-synuclein in neurons. WhenGBA1mutant neurons were treated with GCase replacement or chaperone therapy; cathepsin D protein levels and activity were restored, and monomeric α-synuclein decreased. When cathepsin D was inhibited, GCase replacement failed to reduce monomeric α-synuclein levels inGBA1mutant neurons. These data indicate thatGBA1gene mutations increase monomeric α-synuclein levels via an effect on lysosomal cathepsin D in neurons.