Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine
Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine
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DOI：
10.1007/s00401-007-0303-9
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发表时间：
2008-02-01
影响因子：
12.7
通讯作者：
Galvin, James E.
中科院分区：
文献类型：
--
作者：
Burke, William J.;Kumar, Vijaya B.;Galvin, James E.
帕金森病（PD）是一种神经退行性疾病，其特征在于多巴胺（DA）神经元的选择性丧失和在剩余的黑质（SN）神经元中存在α-突触核蛋白（AS）聚集体作为路易体（LB）。PD发病机制研究中的一个持续难题是，尽管AS在整个大脑中表达，但LB和选择性多巴胺能细胞损失导致PD的特征性临床体征，这表明AS聚集和DA代谢之间存在联系。这种联系的一个潜在候选者是DA的单胺氧化酶（MAO）代谢产物3，4-二羟基苯乙醛（DOPAL），因为DA和除DOPAL以外的DA代谢产物在生理浓度下对SN神经元都没有毒性。我们测试了DOPAL诱导AS聚集在无细胞系统中，在体外DA神经元培养物和立体定向注射到SD大鼠的SN通过Western印迹，荧光共聚焦显微镜和免疫组织化学在体内。我们证明，生理相关浓度的DOPAL会在无细胞系统和细胞培养物中引发AS聚集，导致形成潜在有毒的AS低聚物和聚集体。此外，DOPAL注射到SD大鼠的SN导致DA神经元的损失和高分子量的AS寡聚体的积累通过Western blot检测。我们的研究结果支持这一假设，DA代谢通过DOPAL可以导致DA神经元的损失和AS聚集在PD中观察到的。
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons and the presence of alpha-synuclein (AS) aggregates as Lewy bodies (LBs) in the remaining substantia nigra (SN) neurons. A continuing puzzle in studying PD pathogenesis is that although AS is expressed throughout the brain, LBs and selective dopaminergic cell loss lead to characteristic clinical signs of PD, suggesting that there is a link between AS aggregation and DA metabolism. One potential candidate for this link is the monoamine oxidase (MAO) metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as neither DA nor DA metabolites other than DOPAL are toxic to SN neurons at physiological concentrations. We tested DOPAL-induced AS aggregation in a cell-free system, in vitro in DA neuron cultures and in vivo with stereotactic injections into the SN of Sprague-Dawley rats by Western blots, fluorescent confocal microscopy and immunohistochemistry. We demonstrate that DOPAL in physiologically relevant concentrations, triggers AS aggregation in the cell-free system, and in cell cultures resulting in the formation of potentially toxic AS oligomers and aggregates. Furthermore, DOPAL injection into the SN of Sprague-Dawley rats resulted in DA neuron loss and the accumulation of high molecular weight oligomers of AS detected by Western blot. Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD.