ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.
ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.
复制标题
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
DOI：
10.1016/j.stemcr.2016.01.013
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发表时间：
2016-03-08
影响因子：
5.9
通讯作者：
Wade-Martins R
中科院分区：
文献类型：
--
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
葡萄糖脑苷脂酶基因（GBA）的杂合突变是帕金森病（PD）最常见的遗传风险因素，帕金森病是第二常见的神经退行性疾病。然而，这种关联的分子机制仍然知之甚少。在这里，我们分析了10个独立的诱导多能干细胞（iPSC）系，来自3个对照组和3个不相关的PD患者GBA-N370 S突变杂合子，并确定了相关的疾病机制。在分化成多巴胺能神经元后，我们观察到ER中突变型葡萄糖脑苷脂酶蛋白的错误处理，与ER应激和异常细胞脂质谱的激活相关。此外，我们观察到自噬扰动和扩大的溶酶体室，特别是在多巴胺神经元。最后，我们在患者源性神经元培养基中发现细胞外α-突触核蛋白增加，这与外泌体无关。总体而言，ER应激、自噬/溶酶体扰动和细胞外α-突触核蛋白升高可能代表PD的关键早期细胞表型，这可能提供多种治疗靶点。来自5个PD GBA-N370 S和5个对照iPSC系的多巴胺神经元的功能分析iPSC PD-N370 S多巴胺神经元中的脂质分布、ER应激和自噬iPSC PD-N370 S多巴胺神经元中的溶酶体区室扩大和受损iPSC PD-N370 S多巴胺神经元培养物中的细胞外α-突触核蛋白增加在这篇文章中，Wade-Martins及其同事表明，在帕金森病患者的多巴胺神经元中，GBA-N370 S突变导致GCase的错误处理，ER应激增加和血脂异常。此外，GBA-N370 S突变损害自噬和溶酶体功能，最终导致多巴胺能神经元培养物中α-突触核蛋白释放增加，这可能是帕金森病早期发病机制的核心。
Heterozygous mutations in the glucocerebrosidase gene (GBA) represent the strongest common genetic risk factor for Parkinson's disease (PD), the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC) lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets. Functional analysis of dopamine neurons from 5 PD GBA-N370S and 5 control iPSC lines Perturbed lipid profiles, ER stress, and autophagy in iPSC PD-N370S dopamine neurons Enlarged and impaired lysosomal compartment in iPSC PD-N370S dopamine neurons Increased extracellular α-synuclein in iPSC PD-N370S dopamine neuronal cultures In this article, Wade-Martins and colleagues show that in dopamine neurons from Parkinson's disease patients, the GBA-N370S mutation leads to the misprocessing of GCase, increased ER stress, and abnormal lipid profiles. Further, the GBA-N370S mutation impairs autophagic and lysosomal function, ultimately leading to increased α-synuclein release in dopaminergic neuronal cultures, which may be central in the early pathogenesis of Parkinson's disease.