The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity.
The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity.
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DOI：
10.1371/journal.pgen.1002488
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发表时间：
2012-02
期刊：
影响因子：
4.5
通讯作者：
Schulz JB
中科院分区：
文献类型：
--
作者：
Butler EK;Voigt A;Lutz AK;Toegel JP;Gerhardt E;Karsten P;Falkenburger B;Reinartz A;Winklhofer KF;Schulz JB
α-Synuclein的过表达或突变与蛋白质聚集有关，并干扰许多细胞过程，包括线粒体的完整性和功能。我们利用果蝇的全基因组筛选来寻找人类[A53T]α-突触核蛋白诱导的神经毒性的新的遗传修饰因子。研究发现，线粒体伴侣蛋白肿瘤坏死因子受体相关蛋白-1 （TRAP1）的表达降低会增加蝇头多巴胺（DA）和DA神经元数量的年龄依赖性损失，这是由[A53T]α-Synuclein表达引起的。此外，在表达[A53T]α- synuclein的果蝇中，TRAP1表达降低导致攀爬能力丧失和氧化应激敏感性增强。过表达人TRAP1能够挽救这些表型。同样，人TRAP1在大鼠初级皮质神经元中的过表达挽救了α-突触核蛋白诱导的[A53T]对鱼藤酮的敏感性。在人（非）神经细胞系中，靶向TRAP1的小干扰RNA增强了[A53T]α-突触核蛋白诱导的氧化应激敏感性。[A53T]α-Synuclein在HEK293细胞中表达降低复合物I活性，直接干扰线粒体功能。这些作用被TRAP1过表达阻断。此外，TRAP1能够阻止人SH-SY5Y细胞中[A53T]α-Synuclein过表达引起的线粒体形态改变。这些结果表明[A53T]α-突触核蛋白毒性与线粒体功能障碍密切相关，并且通过线粒体伴侣蛋白TRAP1的过表达可以降低果蝇和大鼠原代神经元和人类细胞系的毒性。有趣的是，TRAP1先前已被丝氨酸/苏氨酸激酶PINK1磷酸化，从而提供了PINK1通过TRAP1与α-Synuclein的潜在联系。帕金森病（PD）是一种进行性神经退行性疾病，病理特征为大脑致密黑质部多巴胺能神经元的丧失。α-突触核蛋白突变或基因复制或三倍复制导致常染色体显性遗传性帕金森病。事实上，聚集性和不溶性α-突触核蛋白在路易体中被发现，这是散发性和遗传性PD的共同病理标志。为了更好地明确α-Synuclein的致病机制，我们首先利用果蝇基因筛选，寻找突变型人[A53T]α-Synuclein神经毒性的新型遗传修饰因子。我们发现线粒体伴侣蛋白TRAP1是[A53T]α-Synuclein诱导的毒性的新修饰物。[A53T]α-突触核蛋白诱导的毒性随着TRAP1表达的降低而增强，而过表达人TRAP1 （hTRAP1）则起到了拯救作用。细胞培养实验进一步证明，[A53T]α-Synuclein直接干扰线粒体的多种功能，包括Complex I ATP的产生、线粒体断裂和对氧化应激的敏感性。这些作用可被TRAP1过表达阻断。由于线粒体功能障碍先前与其他几种与遗传性帕金森病相关的基因突变有关，这些数据进一步证明了帕金森病发病的共同线粒体中心机制。
Overexpression or mutation of α-Synuclein is associated with protein aggregation and interferes with a number of cellular processes, including mitochondrial integrity and function. We used a whole-genome screen in the fruit fly Drosophila melanogaster to search for novel genetic modifiers of human [A53T]α-Synuclein–induced neurotoxicity. Decreased expression of the mitochondrial chaperone protein tumor necrosis factor receptor associated protein-1 (TRAP1) was found to enhance age-dependent loss of fly head dopamine (DA) and DA neuron number resulting from [A53T]α-Synuclein expression. In addition, decreased TRAP1 expression in [A53T]α-Synuclein–expressing flies resulted in enhanced loss of climbing ability and sensitivity to oxidative stress. Overexpression of human TRAP1 was able to rescue these phenotypes. Similarly, human TRAP1 overexpression in rat primary cortical neurons rescued [A53T]α-Synuclein–induced sensitivity to rotenone treatment. In human (non)neuronal cell lines, small interfering RNA directed against TRAP1 enhanced [A53T]α-Synuclein–induced sensitivity to oxidative stress treatment. [A53T]α-Synuclein directly interfered with mitochondrial function, as its expression reduced Complex I activity in HEK293 cells. These effects were blocked by TRAP1 overexpression. Moreover, TRAP1 was able to prevent alteration in mitochondrial morphology caused by [A53T]α-Synuclein overexpression in human SH-SY5Y cells. These results indicate that [A53T]α-Synuclein toxicity is intimately connected to mitochondrial dysfunction and that toxicity reduction in fly and rat primary neurons and human cell lines can be achieved using overexpression of the mitochondrial chaperone TRAP1. Interestingly, TRAP1 has previously been shown to be phosphorylated by the serine/threonine kinase PINK1, thus providing a potential link of PINK1 via TRAP1 to α-Synuclein. Parkinson's disease (PD) is a progressive neurodegenerative disorder, pathologically characterized by loss of dopaminergic neurons in the substantia nigra pars compacta brain region. Mutations in α-Synuclein or gene duplication or triplication result in autosomal-dominant inherited PD. Indeed, aggregated and insoluble α-Synuclein is found in Lewy bodies, a pathological hallmark common to both sporadic and hereditary forms of PD. In order to better define α-Synuclein's pathogenic mechanism, we first used a fly genetic screen to search for novel genetic modifiers of mutant human [A53T]α-Synuclein neurotoxicity. We identified the mitochondrial chaperone protein TRAP1 as a novel modifier of the toxicity induced by [A53T]α-Synuclein. [A53T]α-Synuclein–induced toxicity was enhanced when TRAP1 expression was decreased, while overexpression of human TRAP1 (hTRAP1) provided a rescue. Cell culture experiments further demonstrated that [A53T]α-Synuclein directly interferes with a number of mitochondrial functions, including Complex I ATP production, mitochondrial fragmentation, and sensitivity to oxidative stress. These effects could be blocked by TRAP1 overexpression. As mitochondrial dysfunction has previously been linked to mutations in several other genes associated with genetic PD, these data provide further evidence of a common mitochondrial-centric mechanism of PD pathogenesis.
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影响因子：
3
作者：
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通讯作者：
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影响因子：
14.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1080/10253890701314863
发表时间：
2007-11-01
影响因子：
2.3
作者：
Gesualdi, N. Montesano;Chirico, G.;Esposito, F.
通讯作者：
Esposito, F.