Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c PROTECTION AGAINST APOPTOSIS VERSUS DELAYED OXIDATIVE STRESS IN PARKINSON DISEASE
Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c PROTECTION AGAINST APOPTOSIS VERSUS DELAYED OXIDATIVE STRESS IN PARKINSON DISEASE
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DOI：
10.1074/jbc.m900418200
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发表时间：
2009-06-05
影响因子：
4.8
通讯作者：
Kagan, Valerian E.
中科院分区：
文献类型：
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作者：
Bayir, Huelya;Kapralov, Alexandr A.;Kagan, Valerian E.
突触前线粒体的损伤可导致促凋亡因子的释放，从而威胁整个神经元的完整性。我们发现α-突触核蛋白（Syn）与阴离子脂质（如心磷脂）和细胞色素c形成三重复合物，发挥过氧化物酶活性。后者催化Syn与细胞色素c共价异源寡聚成高分子量聚集体。Syn是该反应的优选底物，并且比心磷脂、多巴胺和其他酚类底物更容易被氧化。共定位的Syn与细胞色素c检测聚集体形成后促凋亡刺激的SH-SY 5 Y和HeLa细胞和多巴胺能黑质神经元鱼藤酮治疗的大鼠。Syn-cardiolipin在无细胞系统中对细胞色素c诱导的caspase-3活化产生保护作用，特别是在H2 O2存在下。将Syn直接递送到小鼠胚胎细胞中赋予了对促凋亡caspase-3活化的抗性。相反，HeLa细胞中Syn的小干扰RNA耗尽使它们对多巴胺诱导的细胞凋亡更敏感。在人类帕金森病黑质神经元中，三分之二的共定位的Syn-cytochrome c复合物发生在路易神经突起。综上所述，这些结果表明，Syn可以通过细胞色素c的共价异源寡聚化来防止神经元中的凋亡的执行。Syn的这种直接保护功能与过氧化物酶复合物的形成有关，该复合物代表氧化应激和延迟损伤的来源。
Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that alpha-synuclein (Syn) forms a triple complex with anionic lipids ( such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Co-localization of Syn with cytochrome c was detected in aggregates formed upon proapoptotic stimulation of SH-SY5Y and HeLa cells and in dopaminergic substantia nigra neurons of rotenone-treated rats. Syn-cardiolipin exerted protection against cytochrome c-induced caspase-3 activation in a cell-free system, particularly in the presence of H2O2. Direct delivery of Syn into mouse embryonic cells conferred resistance to proapoptotic caspase-3 activation. Conversely, small interfering RNA depletion of Syn in HeLa cells made them more sensitive to dopamine-induced apoptosis. In human Parkinson disease substantia nigra neurons, two-thirds of co-localized Syn-cytochrome c complexes occurred in Lewy neurites. Taken together, these results indicate that Syn may prevent execution of apoptosis in neurons through covalent hetero-oligomerization of cytochrome c. This immediate protective function of Syn is associated with the formation of the peroxidase complex representing a source of oxidative stress and postponed damage.