Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease.
Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease.
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DOI：
10.1111/j.1471-4159.2012.07924.x
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发表时间：
2012-12
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;Sullivan R;Gross DJ;Holmes C;Kopin IJ;Sharabi Y
帕金森病导致黑质纹状体多巴胺能末梢的严重丧失，神经元内儿茶酚胺的囊泡摄取减少，以及毒性多巴胺代谢物3，4-二羟基苯乙醛（DOPAL）的壳核组织浓度相对增加。本研究的目的是测试囊泡摄取阻断是否增加内源性DOPAL产生。我们还研究了细胞内DOPAL是否有助于细胞凋亡，并且由于α-突触核蛋白寡聚体可能是帕金森病的致病因素，因此寡聚化α-突触核蛋白。在利血平阻断囊泡摄取后，在PC 12细胞中测定儿茶酚，有或没有抑制代谢DOPAL-大豆苷元的醛脱氢酶和AL 1576的醛还原酶。通过基于6 F-或13 C-多巴胺孵育的方法定量囊泡摄取;通过对外源性多巴胺的细胞凋亡反应（有或没有大豆苷元+AL 1576）来定量DOPAL毒性;以及通过在DOPA孵育期间产生突触核蛋白二聚体来定量DOPAL诱导的突触核蛋白寡聚化，有或没有抑制L-芳香族氨基酸脱羧酶或单胺氧化酶。利血平抑制囊泡摄取95-97%，并迅速增加细胞DOPAL含量（p=0.0008）。大豆黄酮+AL 1576增强了对利血平的DOPAL反应（p=0.004）。细胞内DOPAL促进多巴胺诱导的细胞凋亡和DOPA诱导的突触核蛋白二聚化。研究结果符合“儿茶醛假说”，根据该假说，胞质儿茶酚胺的囊泡隔离减少和儿茶醛解毒受损有助于帕金森病的特征性的儿茶酚胺能去神经支配。
Parkinson disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intra-neuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, since alpha-synuclein oligomers may be pathogenetic in Parkinson disease, oligomerizes alpha-synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPAL—daidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F- or 13C-dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL-induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L-aromatic-amino-acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 95–97% and rapidly increased cell DOPAL content (p=0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p=0.004). Intracellular DOPAL contributed to dopamine-evoked apoptosis and DOPA-evoked synuclein dimerization. The findings fit with the “catecholaldehyde hypothesis,” according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson disease.
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影响因子：
10.4
作者：
Bronstein, Jeff;Carvey, Paul;Chen, Honglei;Cory-Slechta, Deborah;DiMonte, Donato;Duda, John;English, Paul;Goldman, Samuel;Grate, Stephen;Hansen, Johnni;Hoppin, Jane;Jewell, Sarah;Kamel, Freya;Koroshetz, Walter;Langston, James W.;Logroscino, Giancarlo;Nelson, Lorene;Ravina, Bernard;Rocca, Walter;Ross, George W.;Schettler, Ted;Schwarzschild, Michael;Scott, Bill;Seegal, Richard;Singleton, Andrew;Steenland, Kyle;Tanner, Caroline M.;Van Den Eeden, Stephen;Weisskopf, Marc
通讯作者：
Weisskopf, Marc
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
影响因子：
4.2
作者：
Legros, H;Janin, F;Costentin, J
通讯作者：
Costentin, J
影响因子：
2.9
作者：
Ito, Satoru;Nakaso, Kazuhiro;Nakashima, Kenji
通讯作者：
Nakashima, Kenji