α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.
α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.
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α-突触核蛋白与TOM20结合，并抑制在帕金森氏病中进口的线粒体蛋白。
DOI：
10.1126/scitranslmed.aaf3634
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发表时间：
2016-06-08
影响因子：
17.1
通讯作者：
Greenamyre JT
中科院分区：
文献类型：
--
作者：
Di Maio R;Barrett PJ;Hoffman EK;Barrett CW;Zharikov A;Borah A;Hu X;McCoy J;Chu CT;Burton EA;Hastings TG;Greenamyre JT
α-突触核蛋白积累和线粒体功能障碍都与帕金森病（PD）的发病机制密切相关，两者似乎存在相关性。线粒体功能障碍导致α-突触核蛋白的积累和寡聚化，α-突触核蛋白水平升高导致线粒体损伤，但这种双向相互作用的基础尚不清楚。我们现在报道，某些翻译后修饰的α-突触核蛋白以高亲和力结合线粒体蛋白质输入机制的TOM20前序受体，阻止其与其共受体TOM22的相互作用，并损害线粒体蛋白质的输入。因此，线粒体呼吸不足，ROS生成增强，线粒体膜电位丧失。死后PD组织的检查显示，黑质纹状体神经元中α-突触核蛋白：TOM20相互作用异常，与输入线粒体蛋白的丢失有关，从而证实了人类疾病的这一致病过程。在PD体内模型中，适度下调内源性α-突触核蛋白足以维持线粒体蛋白的输入；此外，在体外系统中，TOM20或线粒体靶向信号肽的过表达具有有益的作用并保留了蛋白质的输入。本研究确定了PD的新发病机制，鉴定了α-突触核蛋白野生型的毒性物种，揭示了新的神经保护治疗策略。
α-Synuclein accumulation and mitochondrial dysfunction have both been strongly implicated in the pathogenesis of Parkinson’s disease (PD), and the two appear to be related. Mitochondrial dysfunction leads to accumulation and oligomerization of α-synuclein, and increased levels of α-synuclein cause mitochondrial impairment, but the basis for this bidirectional interaction remains obscure. We now report that certain post-translationally modified species of α-synuclein bind with high-affinity to the TOM20 presequence receptor of the mitochondrial protein import machinery, prevent its interaction with its co-receptor, TOM22, and impair mitochondrial protein import. As a consequence, there is deficient mitochondrial respiration, enhanced ROS production and loss of mitochondrial membrane potential. Examination of postmortem PD tissue reveals an aberrant α-synuclein:TOM20 interaction in nigrostriatal neurons that is associated with loss of imported mitochondrial protein, thereby confirming this pathogenic process in the human disease. Modest knockdown of endogenous α-synuclein was sufficient to maintain mitochondrial protein import in an in vivo model of PD; furthermore, in in vitro systems, overexpression of TOM20 or a mitochondrial targeting signal peptide had beneficial effects and preserved protein import. This study defines a new pathogenic mechanism in PD, identifies toxic species of wildtype α-synuclein, and reveals new therapeutic strategies for neuroprotection.
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影响因子：
6.1
作者：
Mastroberardino PG;Hoffman EK;Horowitz MP;Betarbet R;Taylor G;Cheng D;Na HM;Gutekunst CA;Gearing M;Trojanowski JQ;Anderson M;Chu CT;Peng J;Greenamyre JT
通讯作者：
Greenamyre JT
影响因子：
5.3
作者：
Mosharov, Eugene V.;Staal, Roland G. W.;Sulzer, David
通讯作者：
Sulzer, David
影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
2.6
作者：
Elstner, Matthias;Andreoli, Christophe;Prokisch, Holger
通讯作者：
Prokisch, Holger
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.