Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons
Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons
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DOI：
10.1093/hmg/ddx331
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发表时间：
2017-11-15
影响因子：
3.5
通讯作者：
Wood, Matthew J. A.
中科院分区：
文献类型：
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作者：
Heman-Ackah, Sabrina M.;Manzano, Raquel;Wood, Matthew J. A.
最近从帕金森氏病（PD）患者身上获得的诱导多能干细胞（iPSCs）是由α -突触核蛋白（SNCA）基因位点的三倍复制引起的，这为探索其在帕金森氏病分子发病机制中的作用提供了前所未有的机会。我们使用双缺口CRISPR/Cas9系统在这些细胞中进行SNCA的位点特异性诱变，产生具有标准化SNCA基因剂量的等基因iPSC系。来自这些iPSCs的神经元衍生物的比较基因表达分析揭示了内质网应激表型，其标志是诱导未折叠蛋白反应（UPR）的IRE1 α /XBP1轴并最终导致末端UPR激活。死后脑组织的神经病理学分析表明，pIRE1 α在PD脑中含有高水平α -突触核蛋白或路易小体的神经元内表达。使用这对等基因iPSCs来定义这种表型后，这些细胞可以进一步应用于以uprr为目标的药物发现，以开发疾病修饰疗法。
The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the alpha-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1 alpha/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1 alpha is expressed in PD brains within neurons containing elevated levels of alpha-synuclein or Lewy bodies. Having used this pair of isogenic iPSCs to define this phenotype, these cells can be further applied in UPR-targeted drug discovery towards the development of disease-modifying therapeutics.