Cherny Dmitry, Hoyer Wolfgang, Subramaniam Vinod, Jovin Thomas M
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Goettingen, Germany.
J Mol Biol. 2004 Dec 3;344(4):929-38. doi: 10.1016/j.jmb.2004.09.096.
Filamentous aggregates formed by alpha-synuclein are a prominent and presumably key etiological factor in Parkinson's and other neurodegenerative 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. Histones, 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.
由α-突触核蛋白形成的丝状聚集体是帕金森病及其他以运动障碍为特征的神经退行性疾病中一个突出且可能关键的病因。大量研究表明，各种环境和细胞内因素会影响α-突触核蛋白的纤维化特性，例如通过加速组装过程。组蛋白是染色质的主要成分，它与α-突触核蛋白特异性相互作用并显著增强其纤维化。在此，我们报告染色质的另一种成分，即线性或超螺旋双链DNA（dsDNA），也与野生型α-突触核蛋白相互作用，导致α-突触核蛋白组装成成熟原纤维的过程受到显著刺激，其特征是滞后阶段缩短。一般来说，在线性dsDNA存在的情况下，原纤维的形态保持不变。电子显微镜显示，DNA与原纤维表面结合时形成各种类型的复合物，而双螺旋结构未发生扭曲。这些复合物的存在通过电泳得到证实，电泳还表明一部分结合的DNA对限制性内切酶的消化具有抗性。由α-突触核蛋白突变体A30P和A53T以及C末端截短变体（编码氨基酸残基1 - 108或1 - 124）组装而成的原纤维也与线性dsDNA形成复合物。本文讨论了dsDNA与α-突触核蛋白相互作用的可能机制及意义。
