Dopamine-dependent neurotoxicity of α-synuclein:: A mechanism for selective neurodegeneration in Parkinson disease
Dopamine-dependent neurotoxicity of α-synuclein:: A mechanism for selective neurodegeneration in Parkinson disease
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DOI：
10.1038/nm0602-600
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发表时间：
2002-06-01
期刊：
影响因子：
82.9
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Xu, J;Kao, SY;Yankner, BA
帕金森病（PD）中多巴胺能神经元选择性丧失的机制尚不清楚。本研究表明，α -突触核蛋白在培养的人多巴胺能神经元中的积累导致细胞凋亡，这需要内源性多巴胺的产生，并由活性氧介导。相比之下，α -突触核蛋白对非多巴胺能的人类皮质神经元没有毒性，而是表现出神经保护活性。多巴胺依赖性神经毒性是由含有α -突触核蛋白和14-3-3蛋白的54-83-kD可溶性蛋白复合物介导的，这些蛋白在PD患者的黑质中选择性升高。因此，可溶性α -突触核蛋白复合物的积累可以使内源性多巴胺中毒，这提示了PD中神经元损失选择性的潜在机制。
The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54-83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.