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首页> 外文期刊>The European Journal of Neuroscience >Selective loss of dopaminergic neurons and formation of Lewy body-like aggregations in alpha-synuclein transgenic fly neuronal cultures.
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Selective loss of dopaminergic neurons and formation of Lewy body-like aggregations in alpha-synuclein transgenic fly neuronal cultures.

机译：多巴胺能神经元的选择性损失和阿尔法突触核蛋白转基因果蝇神经元培养物中路易体样聚集的形成。

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摘要

A key pathological feature of Parkinson's disease (PD) is the selective loss of dopaminergic neurons accompanied by the formation of Lewy bodies (LB). Given the complex nature of the disease, it is imperative to develop a model system suitable for molecular and cellular manipulation in order to study the mechanisms underlying the pathogenesis of PD. Here, we report that a new in vitro model of PD has been developed by using Drosophila melanogaster primary neuronal cultures expressing a human mutant alpha-synuclein (alpha-Syn; A30P). The selective loss of dopaminergic (DA) neurons was observed when alpha-Syn was pan-neuronally expressed while non-dopaminergic neurons (e.g. GABAergic) were not influenced. This degeneration was also observed even when alpha-Syn was specifically expressed in DA neurons, demonstrating alpha-Syn toxicity is DA cell-autonomous. In all experiments, cultures 5 days or older showed clear degeneration of DA neurons whereas this degeneration was not significant in 3-day-old cultures. In addition, there were intracellular aggregations in 5-day or older alpha-Syn neurons that were recognized by anti-alpha-Syn or ubiquitin antibodies, demonstrating the formation of LB-like inclusions. By contrast, no such aggregations were found in 3-day-old neurons. The results demonstrate that mutated human alpha-Syn expressed in Drosophila primary neuronal cultures causes the selective loss of DA neurons and the formation of cellular aggregations. Therefore, this is one of the first in vitro models recapitulating two important cellular features of PD and will be useful in examining mechanisms underlying selective neurodegeneration mediated by alpha-Syn.
机译：帕金森氏病（PD）的关键病理特征是多巴胺能神经元的选择性丢失，并伴有路易体（LB）的形成。考虑到该疾病的复杂性，迫切需要开发一种适用于分子和细胞操作的模型系统，以研究PD发病机理的基础。在这里，我们报道通过使用表达人突变体α-突触核蛋白（α-Syn; A30P）的果蝇原代神经元培养物，已经开发了PD的新的体外模型。当泛神经元表达α-Syn时观察到多巴胺能（DA）神经元的选择性丢失，而非多巴胺能神经元（例如GABAergic）不受影响。即使当α-Syn在DA神经元中特异性表达时，也观察到这种变性，这表明α-Syn毒性是DA细胞自主的。在所有实验中，5天或更早的培养物均显示DA神经元明显变性，而这种退化在3天龄的培养物中并不明显。此外，在5天或更久的α-Syn神经元中存在细胞内聚集，被抗α-Syn或泛素抗体识别，表明形成了LB样内含物。相比之下，在3天大的神经元中未发现此类聚集。结果表明，在果蝇原代神经元培养物中表达的突变的人α-Syn引起DA神经元的选择性丢失和细胞聚集的形成。因此，这是概括PD的两个重要细胞特征的首批体外模型之一，将对检查由alpha-Syn介导的选择性神经变性的机制有用。

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