LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
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DOI：
10.1016/j.stem.2011.01.013
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发表时间：
2011-03-04
期刊：
影响因子：
23.9
通讯作者：
Pera RR
中科院分区：
文献类型：
--
作者：
Nguyen HN;Byers B;Cord B;Shcheglovitov A;Byrne J;Gujar P;Kee K;Schüle B;Dolmetsch RE;Langston W;Palmer TD;Pera RR
帕金森氏病(PD)的研究由于无法接触到受影响的人多巴胺(DA)能神经元而受到极大阻碍。在这里，我们报告了一种诱导多能干细胞的产生，该干细胞携带富亮氨酸重复蛋白激酶-2(LRRK2)基因中的p.G2019S突变(G2019S-IPSCs)，这是最常见的PD相关突变。我们证明这些G2019S-IPSCs能够分化为DA神经元，并显示关键的氧化应激反应基因和α-突触核蛋白的表达增加。此外，与未受影响的DA神经元相比，G2019S突变的DA神经元对过氧化氢、MG-132和6-羟基多巴胺引起的caspase-3激活更为敏感。这些发现表明，G2019S-IPSC来源的DA神经元表现出与帕金森病相关的早期表型。由于LRRK2突变的高度外显性及其临床上与散发性帕金森病的相似性，这些神经元可能为识别新的药理药物和诊断提供了一个有价值的平台，用于建模和缓解疾病表型的亚组。
Studies of Parkinson’s disease (PD) have been greatly hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation. We demonstrate that these G2019S-iPSCs were able to differentiate into DA neurons and showed increased expression of key oxidative stress response genes and α-synuclein protein. Moreover, G2019S-mutant DA neurons were more sensitive to caspase-3 activation, caused by exposure to hydrogen peroxide, MG-132, and 6-hydroxydopamine, compared to unaffected DA neurons. These findings suggest that G2019S-iPSC-derived DA neurons exhibit early phenotypes linked to PD. Due to high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD, these neurons may provide a valuable platform for identification of novel pharmacological agents and diagnostics for modeling and alleviation of a subset of disease phenotypes.
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