Vesicle permeabilization by protofibrillar α-synuclein:: Implications for the pathogenesis and treatment of Parkinson's disease
Vesicle permeabilization by protofibrillar α-synuclein:: Implications for the pathogenesis and treatment of Parkinson's disease
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DOI：
10.1021/bi0102398
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发表时间：
2001-07-03
期刊：
影响因子：
2.9
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Volles, MJ;Lee, SJ;Lansbury, PT
纤维状α-突触核蛋白是路易体的一种成分，路易体是帕金森病（PD）脑的特征性神经元包涵体。与常染色体显性早发性PD相关的两种α-突触核蛋白突变均促进天然未折叠蛋白在体外转化为有序的前原纤维寡聚体，表明这些原纤维而不是原纤维本身可能诱导细胞死亡。我们在这里报告说，原纤维显着不同的纤维就其与合成膜的相互作用。与单体和纤维形式相反，原纤维α-突触核蛋白通过富含β-片层的结构非常紧密地结合合成囊泡，并短暂地透化这些囊泡。用原子力显微镜直接观察到原纤维α-突触核蛋白对囊泡膜的破坏。α-突触核蛋白纤维化的毒性可能来源于寡聚中间体而不是原纤维，这一可能性对PD治疗剂的设计具有影响。
Fibrillar alpha -synuclein is a component of the Lewy body, the characteristic neuronal inclusion of the Parkinson's disease (PD) brain. Both alpha -synuciein mutations linked to autosomal dominant early-onset forms of PD promote the in vitro conversion of the natively unfolded protein into ordered prefibrillar oligomers, suggesting that these protofibrils, rather than the fibril itself, may induce cell death. We report here that protofibrils differ markedly from fibrils with respect to their interactions with synthetic membranes. Protofibrillar alpha -synuclein, in contrast to the monomeric and the fibrillar forms, binds synthetic vesicles very tightly via a beta -sheet-rich structure and transiently permeabilizes these vesicles. The destruction of vesicular membranes by protofibrillar alpha -synuclein was directly observed by atomic force microscopy. The possibility that the toxicity of alpha -synuclein fibrillization may derive from an oligomeric intermediate, rather than the fibril, has implications regarding the design of therapeutics for PD.