Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death
Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death
复制标题
DOI：
10.1111/j.1471-4159.2006.03815.x
复制
发表时间：
2006-07-01
影响因子：
4.7
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
--
作者：
Yamashita, H;Nakamura, T;Matsumoto, M
用小鼠胚胎干细胞建立帕金森病（PD）神经元模型。建立过表达小鼠核受体相关1（Nurr 1）以及人野生型和丙氨酸30 ->脯氨酸（A30 P）和丙氨酸53 ->苏氨酸（A53 T）突变体α-突触核蛋白的ES细胞系，并使其分化为多巴胺能神经元。表达野生型或突变型α-突触核蛋白的ES细胞衍生的多巴胺能神经元表现出与黑质多巴胺能神经元一致的基本特征。ES细胞来源的PD模型神经元表现出对氧化应激、蛋白酶体抑制和线粒体抑制的敏感性增加。PD模型神经元和对照神经元的细胞活力相似，直到分化后28天。尽管如此，在该时间之后，PD模型神经元在1个月的过程中逐渐开始经历神经元死亡，显示细胞质聚集体形成和不溶性α-突触核蛋白的增加。这种迟发性神经元死亡以突变体α-突触核蛋白水平依赖的方式观察到，其被c-jun N-末端激酶抑制剂和半胱天冬酶抑制剂轻微抑制。当相同的ES细胞系分化成少突胶质细胞时，未观察到这种细胞死亡。ES细胞衍生的PD模型神经元被认为是一种新的原型建模PD，将允许更好地调查潜在的神经退行性病理生理学的前瞻性候选人。
Establishment of a Parkinson's disease (PD) neuron model was attempted with mouse embryonic stem (ES) cells. ES cell lines over-expressing mouse nuclear receptor-related 1 (Nurr1), together with human wild-type and alanine 30 -> proline (A30P) and alanine 53 -> threonine (A53T) mutant alpha-synuclein were established and subjected to differentiation into dopaminergic neurons. The ES cell-derived dopaminergic neurons expressing wild-type or mutant alpha-synuclein exhibited the fundamental characteristics consistent with dopaminergic neurons in the substantia nigra. The ES cell-derived PD model neurons exhibited increased susceptibility to oxidative stress, proteasome inhibition, and mitochondrial inhibition. Cell viability of PD model neurons and the control neurons was similar until 28 days after differentiation. Nonetheless, after that time, PD model neurons gradually began to undergo neuronal death over the course of 1 month, showing cytoplasmic aggregate formation and an increase of insoluble alpha-synuclein protein. Such delayed neuronal death was observed in a mutant alpha-synuclein protein level-dependent manner, which was slightly inhibited by a c-jun N-terminal kinase inhibitor and a caspase inhibitor. Such cell death was not observed when the same ES cell lines were differentiated into oligodendrocytes. The ES cell-derived PD model neurons are considered as prospective candidates for a new prototype modelling PD that would allow better investigation of the underlying neurodegenerative pathophysiology.