α-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils
α-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils
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DOI：
10.1016/s0022-2836(02)00735-0
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发表时间：
2002-10-04
影响因子：
5.6
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Lashuel, HA;Petre, BM;Lansbury, PT
α-突触核蛋白基因中的两个突变（A30 P和A53 T）与常染色体显性遗传早发性帕金森病（PD）有关。这两种突变都促进了瞬时原纤维（前原纤维寡聚体）的形成，表明原纤维与细胞毒性有关。在这项工作中，使用电子显微镜和数字图像处理研究了这些突变对α-突触核蛋白寡聚体结构的影响。观察到PD连锁突变（A30 P和A53 T）影响α-突触核蛋白原纤维的形态和大小分布（通过分析性超离心和扫描透射电子显微镜测量）。观察到A30 P变体促进环状孔样原纤维的形成，而A53 T促进环状和管状原纤维结构的形成。野生型α-突触核蛋白也形成环状原纤维，但仅在延长孵育后。孔样寡聚体结构的形成可以解释α-突触核蛋白原纤维的膜透化活性。这些结构可能有助于PD的发病机制。(C)2002爱思唯尔科技有限公司版权所有。
Two mutations in the alpha-synuclein gene (A30P and A53T) have been linked to autosomal dominant early-onset Parkinson's disease (PD). Both mutations promote the formation of transient protofibrils (prefibrillar oligomers), suggesting that protofibrils are linked to cytotoxicity. In this work, the effect of these mutations on the structure of alpha-synuclein oligomers was investigated using electron microscopy and digital image processing. The PD-linked mutations (A30P and A53T) were observed to affect both the morphology and the size distribution of alpha-synuclein protofibrils (measured by analytical ultracentrifugation and scanning transmission electron microscopy). The A30P variant was observed to promote the formation of annular, pore-like protofibrils, whereas A53T promotes formation of annular and tubular protofibrillar structures. Wild-type alpha-synuclein also formed annular protofibrils, but only after extended incubation. The formation of pore-like oligomeric structures may explain the membrane permeabilization activity of alpha-Synuclein protofibrils. These structures may contribute to the pathogenesis of PD. (C) 2002 Elsevier Science Ltd. All rights reserved.