Rapid anionic micelle-mediated α-synuclein fibrillization in vitro
Rapid anionic micelle-mediated α-synuclein fibrillization in vitro
复制标题
DOI：
10.1074/jbc.m308231200
复制
发表时间：
2003-11-21
影响因子：
4.8
通讯作者：
Kuret, J
中科院分区：
文献类型：
--
作者：
Necula, M;Chirita, CN;Kuret, J
帕金森病的特征是 α-突触核蛋白在受影响的基底神经节神经元内聚集成丝状形式。纯化的重组α-突触核蛋白的纤维化在体外效率较低，但可以通过添加包括糖胺聚糖和聚阳离子在内的各种试剂来增强。在这里，我们报道脂肪酸和结构相关的阴离子去污剂在低微摩尔浓度下极大地加速重组α-突触核蛋白的纤维化，滞后时间短至11分钟，表观一级生长速率常数快至10.4小时(-1)。所有去污剂和脂肪酸在活性浓度下都是胶束，因为它们的临界胶束浓度依赖于α-突触核蛋白。其他阴离子表面，例如由阴离子磷脂囊泡提供的表面，也诱导α-突触核蛋白原纤维化，并产生源自其表面的丝。这些数据表明，以胶束或囊泡形式存在的阴离子表面可以使α-突触核蛋白纤维化成核，这种机制是阴离子表面活性剂诱导剂活性的基础，并且阴离子膜可以在体内发挥这种功能。
Parkinson's disease is characterized by the aggregation of alpha-synuclein into filamentous forms within affected neurons of the basal ganglia. Fibrillization of purified recombinant alpha-synuclein is inefficient in vitro but can be enhanced by the addition of various agents including glycosaminoglycans and polycations. Here we report that fatty acids and structurally related anionic detergents greatly accelerate fibrillization of recombinant alpha-synucleinat low micromolar concentrations with lag times as short as 11 min and apparent first order growth rate constants as fast as 10.4 h(-1). All detergents and fatty acids were micellar at active concentrations because of an alpha-synuclein-dependent depression of their critical micelle concentrations. Other anionic surfaces, such as those supplied by anionic phospholipid vesicles, also induced alpha-synuclein fibrillization, with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate alpha-synuclein fibrillization, that this mechanism underlies the inducer activity of anionic surfactants, and that anionic membranes may serve this function in vivo.