Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease
Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease
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DOI：
10.1074/jbc.274.41.28849
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发表时间：
1999-10-08
影响因子：
4.8
通讯作者：
Masliah, E
中科院分区：
文献类型：
--
作者：
Hashimoto, M;Takeda, A;Masliah, E
α-突触核蛋白是在路易体疾病和其它神经变性疾病中形成淀粉样原纤维的聚集体的主要成分，但对α-突触核蛋白在神经变性过程中细胞内聚集的机制知之甚少。最近的研究表明，氧化应激反应可能有助于这种分子的异常聚集。在这种情况下，本研究的主要目的是确定血红素蛋白细胞色素c在α-突触核蛋白聚集的潜在作用。当重组α-突触核蛋白与细胞色素c/过氧化氢共孵育时，α-突触核蛋白伴随诱导聚集。这一过程被抗氧化剂如N-乙酰-L-半胱氨酸阻断。氯化高铁血红素/过氧化氢同样诱导α-突触核蛋白的聚集，细胞色素c/过氧化氢和氯化高铁血红素/过氧化氢诱导的α-突触核蛋白的聚集被部分抑制与铁螯合剂去铁胺治疗。这表明，铁催化的细胞色素c/过氧化氢介导的氧化反应可能是至关重要的参与促进α-突触核蛋白聚集。此外，细胞色素c/α-突触核蛋白的双标记研究表明，他们共定位于路易体的帕金森病患者的diseases.Taken在一起，这些结果表明，细胞色素c，一个众所周知的电子传递，和介导的凋亡细胞死亡可能参与氧化应激诱导的聚集的α-突触核蛋白在帕金森病和相关疾病。
alpha-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which alpha-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in alpha-synuclein aggregation. When recombinant alpha-synuclein was coincubated with cytochrome c/hydrogen peroxide, alpha-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/hydrogen peroxide similarly induced aggregation of alpha-synuclein, and both cytochrome c/hydrogen peroxide- and hemin/hydrogen peroxide-induced aggregation of alpha-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that iron-catalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting alpha-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/alpha-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease.Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stress-induced aggregation of alpha-synuclein in Parkinson's disease and related disorders.