Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.
Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease.
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DOI：
10.1111/jnc.13042
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发表时间：
2015-04
影响因子：
4.7
通讯作者：
Sharabi Y
中科院分区：
文献类型：
--
作者：
Goldstein DS;Sullivan P;Cooney A;Jinsmaa Y;Kopin IJ;Sharabi Y
重复全身施用线粒体复合物I抑制剂鱼藤酮产生帕金森病（PD）的啮齿动物模型。相对选择性鱼藤酮诱导的黑质纹状体多巴胺能神经元损伤的机制仍不完全清楚。根据“儿茶酚醛假说”，自毒多巴胺代谢物3，4-二羟基苯乙醛（DOPAL）的积累有助于PD发病机制。囊泡摄取阻断增加DOPAL水平，DOPAL主要通过醛脱氢酶（ALDH）解毒。我们测试鱼藤酮是否干扰囊泡摄取和细胞内ALDH活性。在与鱼藤酮（0-1000 nM，180分钟）孵育的PC 12细胞中测量内源性和F-标记的儿茶酚，不含或含F-多巴胺（2 μM），以跟踪囊泡摄取和儿茶酚胺代谢。鱼藤酮剂量依赖性地增加DOPAL，F-DOPAL和3，4-二羟基苯基乙醇（DOPET）水平，同时降低多巴胺和3，4-二羟基苯乙酸（DOPAC）水平以及多巴胺与其脱氨基代谢产物总和的比率。在试管中，鱼藤酮没有影响DOPAL DOPAC的转化ALDH时，NAD+供应，而直接作用的ALDH抑制剂苯菌灵显着增加DOPAL和DOPAC浓度降低反应混合物。我们认为鱼藤酮通过降低ALDH活性和减弱胞质儿茶酚胺的囊泡隔离来建立细胞内DOPAL。这一结果为鱼藤酮对多巴胺能神经元的选择性毒性提供了新的机制。
Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson disease (PD). Mechanisms of relatively selective rotenone-induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. According to the “catecholaldehyde hypothesis,” buildup of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to PD pathogenesis. Vesicular uptake blockade increases DOPAL levels, and DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH). We tested whether rotenone interferes with vesicular uptake and intracellular ALDH activity. Endogenous and F-labeled catechols were measured in PC12 cells incubated with rotenone (0-1000 nM, 180 minutes), without or with F-dopamine (2 μM) to track vesicular uptake and catecholamine metabolism. Rotenone dose-dependently increased DOPAL, F-DOPAL, and 3,4-dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the sum of its deaminated metabolites. In test tubes, rotenone did not affect conversion of DOPAL to DOPAC by ALDH when NAD+ was supplied, whereas the direct-acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC concentrations in the reaction mixtures. We propose that rotenone builds up intracellular DOPAL by decreasing ALDH activity and attenuating vesicular sequestration of cytoplasmic catecholamines. The results provide a novel mechanism for selective rotenone-induced toxicity in dopaminergic neurons.
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影响因子：
5.2
作者：
Eiden LE;Weihe E
通讯作者：
Weihe E
影响因子：
--
作者：
Kazantsev, Aleksey G.;Kolchinsky, Alexander M.
通讯作者：
Kolchinsky, Alexander M.
影响因子：
11.2
作者：
HALLIDAY, GM;LI, YW;GEFFEN, LB
通讯作者：
GEFFEN, LB
帕金森病中有毒多巴胺代谢物 DOPAL 积累的决定因素。
影响因子：
4.7
作者：
Goldstein DS;Sullivan P;Holmes C;Miller GW;Alter S;Strong R;Mash DC;Kopin IJ;Sharabi Y
通讯作者：
Sharabi Y
影响因子：
4.1
作者：
Meyer, MJ;Mosely, DE;Picklo, MJ
通讯作者：
Picklo, MJ