Double-stranded DNA stimulates the fibrillation of α-synuclein in vitro and is associated with the mature fibrils:: An electron microscopy study
Double-stranded DNA stimulates the fibrillation of α-synuclein in vitro and is associated with the mature fibrils:: An electron microscopy study
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DOI：
10.1016/j.jmb.2004.09.096
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发表时间：
2004-12-03
影响因子：
5.6
通讯作者：
Jovin, TM
中科院分区：
文献类型：
--
作者：
Cherny, D;Hoyer, W;Jovin, TM
由α-突触核蛋白形成的丝状体聚集体是帕金森病和以运动障碍为特征的其他神经退行性疾病中的突出且可能是关键的病因因素。许多研究已经证明，各种环境和细胞内因素影响α-突触核蛋白的原纤化性质，例如通过加速组装过程。Histories是染色质的主要成分和组成部分，与α-突触核蛋白特异性相互作用并显著增强其纤维化。在这里，我们报告，染色质的另一个组成部分，双链DNA（dsDNA），无论是线性或超螺旋，也与野生型α-突触核蛋白相互作用，导致一个显着的刺激α-突触核蛋白组装成成熟的原纤维，其特征在于减少滞后期。通常，在线性dsDNA存在下，原纤维的形态保持不变。电子显微镜显示，DNA形成各种类型的复合物后，协会与原纤维在其表面没有扭曲的双螺旋结构。这些复合物的存在被证实的电泳，这也表明，相关的DNA的一部分是耐消化的限制性内切酶。由α-突触核蛋白突变体A30 P和A53 T以及C-末端截短的变体（编码氨基酸残基1-108或1-124）组装的原纤维也与线性dsDNA形成复合物。dsDNA-alpha-synuclein相互作用的可能机制和影响进行了讨论。(C)2004爱思唯尔有限公司保留所有权利。
Filamentous aggregates formed by a-synuclein are a prominent and presumably key etiological factor in Parkinson's and other neuro-degenerative diseases characterized by motor disorders. Numerous studies have demonstrated that various environmental and intracellular factors affect the fibrillation properties of alpha-synuclein, e.g. by accelerating the process of assembly. Histories, the major component and constituent of chromatin, interact specifically with alpha-synuclein and enhance its fibrillation significantly. Here, we report that another component of chromatin, double-stranded DNA (dsDNA), either linear or supercoiled, also interacts with wild-type alpha-synuclein, leading to a significant stimulation of alpha-synuclein assembly into mature fibrils characterized by a reduced lag phase. In general, the morphology of the fibrils remains unchanged in the presence of linear dsDNA. Electron microscopy reveals that DNA forms various types of complexes upon association with the fibrils at their surface without distortion of the double-helical structure. The existence of these complexes was confirmed by the electrophoresis, which also demonstrated that a fraction of the associated DNA was resistant to digestion by restriction endonucleases. Fibrils assembled from the alpha-synuclein mutants A30P and A53T and the C-terminally truncated variants (encoding amino acid residues 1-108 or 1-124) also form complexes with linear dsDNA. Possible mechanisms and implications of dsDNA-alpha-synuclein interactions are discussed. (C) 2004 Elsevier Ltd. All rights reserved.