Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration
Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration
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DOI：
10.1073/pnas.1318830110
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发表时间：
2013-11-26
影响因子：
11.1
通讯作者：
Bennett, Joan Wennstrom
中科院分区：
文献类型：
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作者：
Inamdar, Arati A.;Hossain, Muhammad M.;Bennett, Joan Wennstrom
帕金森病（PD）是最常见的运动障碍，虽然确切原因尚不清楚，但最近的流行病学和实验研究表明，几种环境因素可能是重要的危险因素。迄今为止，这些可疑的环境风险因素一直是人造化学品。在本报告中，我们通过遗传学、生化和免疫学研究证明，常见的挥发性真菌半化学物质1-辛烯-3-醇降低了黑胃果蝇的多巴胺水平，导致多巴胺神经元变性。囊泡单胺转运蛋白（VMAT）的过度表达挽救了多巴胺毒性和神经变性，而VMAT和酪氨酸羟化酶的突变则加剧了毒性。此外，1-辛烯-3-醇还能抑制表达人质膜多巴胺转运蛋白（DAT）和人VMAT同源物VMAT2的人细胞系对多巴胺的摄取。这些数据表明，1-辛烯-3-醇通过破坏多巴胺稳态发挥毒性，可能是一种自然发生的环境因子，与帕金森病有关。
Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism.