Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways.
Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways.
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DOI：
10.1016/j.nbd.2014.11.018
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发表时间：
2015-09
影响因子：
6.1
通讯作者：
Franco, Rodrigo
中科院分区：
文献类型：
--
作者：
Anandhan, Annadurai;Rodriguez-Rocha, Humberto;Bohovych, Iryna;Griggs, Amy M.;Zavala-Flores, Laura;Reyes-Reyes, Elsa M.;Seravalli, Javier;Stanciu, Lia A.;Lee, Jaekwon;Rochet, Jean-Christophe;Khalimonchuk, Oleh;Franco, Rodrigo
关键词：
α-突触核蛋白的基因倍增或点突变与家族性和散发性帕金森病（PD）相关。据报道，PD患者的脑脊液和血液中铜（Cu）水平增加，而职业暴露于Cu已被认为增加了发展PD的风险。我们的目的是阐明α-突触核蛋白和铜调节多巴胺能细胞死亡的机制。WT或A53 T α-突触核蛋白的短期过表达在人多巴胺能细胞和原代中脑培养物中没有毒性作用，但对Cu诱导的细胞死亡具有协同作用。铜诱导的细胞死亡是由铜转运蛋白1（Ctr 1）的过度表达和细胞内谷胱甘肽（GSH）的耗竭，表明铜的毒性作用与其细胞内稳态的改变增强。使用氧化还原传感器roGFP，我们证明，铜诱导的氧化应激主要定位在细胞质中，而不是在线粒体。然而，α-synuclein过表达对Cu诱导的氧化应激没有影响。WT或A53 T α-突触核蛋白过表达在不存在α-突触核蛋白聚集的情况下加重了多巴胺能细胞和酵母中的Cu毒性。铜增加自噬通量和蛋白质泛素化。通过显性负性Atg 5形式的过表达或用MG 132抑制泛素/蛋白酶体系统（UPS）来损害自噬增强了Cu诱导的细胞死亡。然而，只有抑制UPS刺激铜和α-突触核蛋白过表达的协同毒性作用。我们的研究结果表明，α-突触核蛋白刺激铜毒性多巴胺能细胞独立于其聚集通过调节蛋白质降解途径。
Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson’s disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of WT or A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic cells and yeast in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways.
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DOI：
10.1016/j.bbamcr.2012.06.019
发表时间：
2012-10
影响因子：
5.1
作者：
Circu, Magdalena L.;Aw, Tak Yee
通讯作者：
Aw, Tak Yee
影响因子：
3.4
作者：
Cheung, Yuen-Ting;Lau, Way Kwok-Wai;Chang, Raymond Chuen-Chung
通讯作者：
Chang, Raymond Chuen-Chung
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
5.4
作者：
Cook, Casey;Stetler, Caroline;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard