The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity
The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity
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DOI：
10.1523/jneurosci.20-16-06048.2000
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发表时间：
2000-08-15
影响因子：
5.3
通讯作者：
Wolozin, B
中科院分区：
文献类型：
--
作者：
Ostrerova-Golts, N;Petrucelli, L;Wolozin, B
帕金森病（PD）是影响老年人的最常见的运动障碍。 PD的特征是路易体的形成和多巴胺能神经元的死亡。 PD 的机制尚不清楚，但 α-突触核蛋白突变可导致家族性 PD 以及 α-突触核蛋白在路易体中积累的发现表明 α-突触核蛋白参与 PD 的病理生理学。利用过度表达野生型、A53T 或 A30P α-突触核蛋白的人类 BE-M17 神经母细胞瘤细胞，我们现在发现铁和自由基产生剂（例如多巴胺或过氧化氢）可刺激含有 α-突触核蛋白和泛素的细胞内聚集物的产生。可以通过免疫细胞化学、电子显微镜或组织化学染色硫黄素 S 来鉴定聚集体。细胞中发生的聚集量取决于表达的 α-突触核蛋白的量和表达的 α-突触核蛋白的类型，其中 α-突触核蛋白聚集的量遵循 A53T > A30P > 野生型 > 未转染的排序顺序。除了刺激聚集体形成外，α-突触核蛋白似乎还会引起毒性。过度表达 α-突触核蛋白的 BE-M17 神经母细胞瘤细胞对铁诱导的毒性的脆弱性增加了四倍。该漏洞遵循与聚合相同的排名顺序。这些数据提出了以下可能性：α-突触核蛋白与铁和多巴胺协同作用，诱导帕金森病中路易体病理的形成和帕金森病中的细胞死亡。
Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.