Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism.
Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism.
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DOI：
10.1021/bi0121353
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发表时间：
2002-03
期刊：
影响因子：
2.9
通讯作者：
Michael J. Volles;P. Lansbury
中科院分区：
文献类型：
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作者：
Michael J. Volles;P. Lansbury
蛋白质 α-突触核蛋白（A30P 和 A53T）的两个突变与常染色体显性遗传的帕金森病有关。这两种突变都加速了体外前原纤维寡聚体（原原纤维）的形成，但它们促进毒性的机制尚不清楚。野生型 α-突触核蛋白的原纤维结合并透化酸性磷脂囊泡。本研究检查了原纤维 α-突触核蛋白野生型、突变体和小鼠变体的相对膜透化活性以及膜透化机制。原纤维 A30P、A53T 和小鼠变体均被发现比野生型蛋白具有更高的每摩尔透化活性。原纤维α-突触核蛋白诱导的囊泡内容物的渗漏表现出对低分子量分子的强烈偏好，表明了类似孔的透化机制。在囊泡膜不稳定的条件下（缺乏钙作为磷脂抗衡离子），原纤维透化的尺寸选择性较小，单体 α-突触核蛋白可以通过类似去污剂的机制进行透化。我们得出的结论是，帕金森病的发病机制可能涉及原纤维α-突触核蛋白的膜透化，其程度很大程度上取决于体内条件。
Two mutations in the protein alpha-synuclein (A30P and A53T) are linked to an autosomal dominant form of Parkinson's disease. Both mutations accelerate the formation of prefibrillar oligomers (protofibrils) in vitro, but the mechanism by which they promote toxicity is unknown. Protofibrils of wild-type alpha-synuclein bind and permeabilize acidic phospholipid vesicles. This study examines the relative membrane permeabilizing activities of the wild type, mutant, and mouse variants of protofibrillar alpha-synuclein and the mechanism of membrane permeabilization. Protofibrillar A30P, A53T, and mouse variants were each found to have greater permeabilizing activities per mole than the wild-type protein. The leakage of vesicular contents induced by protofibrillar alpha-synuclein exhibits a strong preference for low-molecular mass molecules, suggesting a pore-like mechanism for permeabilization. Under conditions in which the vesicular membrane is less stable (lack of calcium as a phospholipid counterion), protofibril permeabilization is less size-selective and monomeric alpha-synuclein can permeabilize via a detergent-like mechanism. We conclude that the pathogenesis of Parkinson's disease may involve membrane permeabilization by protofibrillar alpha-synuclein, the extent of which will be strongly dependent on the in vivo conditions.