Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson's Disease.
Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson's Disease.
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DOI：
10.1371/journal.pone.0164465
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Witt SN
中科院分区：
文献类型：
--
作者：
Wang S;Zhang S;Xu C;Barron A;Galiano F;Patel D;Lee YJ;Caldwell GA;Caldwell KA;Witt SN
我们一直在研究磷脂酰乙醇胺（PE）和磷脂酰胆碱（PC）含量在调节帕金森病蛋白α-突触核蛋白（α-syn）的溶解度中的作用，使用酿酒酵母和秀丽隐杆线虫。合成PE的一种酶是保守的磷脂酰丝氨酸脱羧酶（Psd 1/酵母; PSD-1/蠕虫），它位于线粒体内膜中。我们以前发现，由于Psd 1/psd-1的敲低而降低PE水平会影响体内α-syn的稳态。In S.在酿酒酵母中，psd 1 Δ细胞中低PE和α-syn的共同出现触发线粒体缺陷、内质网应激、糖基磷脂酰肌醇锚定蛋白的错误加工以及α-syn水平的3倍增加。本研究的目的是确定拯救这种表型的药物。我们使用psd 1 Δ + α-syn细胞筛选了1121种食品和药物管理局批准的药物的Prestwick文库，并确定了环孢菌素A、盐酸甲哌沙酯和磺胺苯吡唑为推定的保护性化合物。这些药物的保护活性用C.其中α-syn在多巴胺能神经元中特异性表达，psd-1被RNAi耗尽。在psd-1敲低后检查蠕虫种群的多巴胺能神经元存活。暴露于环孢菌素、甲哌沙酯和磺胺苯吡唑显著提高了表达α-syn的蠕虫种群在第7天的存活率，其中50-55%的种群显示出正常的神经元，相比之下，仅10-15%的未处理动物。我们还发现，所有三种药物都拯救了多巴胺能神经元中表达α-syn的蠕虫，这些神经元在通过RNAi耗尽心磷脂合酶（crls-1）后缺乏磷脂心磷脂。我们讨论了这些药物如何阻断多巴胺能神经元中的α-syn病理。
We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson’s disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50–55% of the populations displayed normal neurons, compared to only 10–15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.
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影响因子：
7.7
作者：
Darios, Frederic;Ruiperez, Violeta;Davletov, Bazbek
通讯作者：
Davletov, Bazbek
影响因子：
2.9
作者：
Hansson, MJ;Persson, T;Elmér, E
通讯作者：
Elmér, E
影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
2.5
作者：
Kara E;Lewis PA;Ling H;Proukakis C;Houlden H;Hardy J
通讯作者：
Hardy J
DOI：
10.1073/pnas.0711018105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Hamamichi, Shusei;Rivas, Renee N.;Caldwell, Guy A.
通讯作者：
Caldwell, Guy A.