A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism
A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism
复制标题
一种新型葡糖脑苷脂伴侣能降低戈谢病和帕金森病患者 iPSC 培养的多巴胺能神经元中的α-突触核蛋白和糖脂水平
DOI：
10.1523/jneurosci.0636-16.2016
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发表时间：
2016-07-13
影响因子：
5.3
通讯作者：
Sidransky, Ellen
中科院分区：
文献类型：
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作者：
Aflaki, Elma;Borger, Daniel K.;Sidransky, Ellen
在帕金森病的已知遗传风险因素中，GBA 1（负责溶酶体疾病戈谢病的基因）突变是最常见的。这种遗传联系使人们注意到溶酶体在帕金森病发病机制中的作用。为了研究葡萄糖脑苷脂酶如何影响帕金森综合征并评估新的治疗方法，我们从4名1型（非神经元病性）戈谢病患者（2名患有帕金森综合征，2名没有帕金森综合征）和1名2型（急性神经元病性）戈谢病患者中产生了诱导的人多能干细胞，并将其分化为巨噬细胞和多巴胺能神经元。这些细胞表现出葡萄糖脑苷脂酶活性降低，并储存糖脂底物葡萄糖神经酰胺和葡萄糖鞘氨醇，证明其与戈谢病患者的相似性。2型和1型戈谢病伴帕金森综合征患者的多巴胺能神经元多巴胺储存和多巴胺转运蛋白再摄取减少。α-突触核蛋白（一种在帕金森病和相关突触核蛋白病中以聚集体形式存在的蛋白质）的水平在帕金森综合征或2型戈谢病患者的神经元中选择性升高。然后用NCGC 607处理细胞，NCGC 607是通过高通量筛选和药物化学结构优化鉴定的葡萄糖脑苷脂酶的小分子非抑制性伴侣。该化合物成功地陪伴突变酶，恢复葡萄糖脑苷脂酶活性和蛋白质水平，并减少iPSC衍生的巨噬细胞和多巴胺能神经元中的糖脂储存，表明其治疗神经元病戈谢病的潜力。此外，NCGC 607降低了帕金森综合征患者多巴胺能神经元中的α-突触核蛋白水平，表明葡萄糖脑苷脂酶的非抑制性小分子伴侣可能被证明可用于治疗帕金森病。
Among the known genetic risk factors for Parkinson disease, mutations in GBA1, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of alpha-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced alpha-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease.