GM1 specifically interacts with α-synuclein and inhibits fibrillation
GM1 specifically interacts with α-synuclein and inhibits fibrillation
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DOI：
10.1021/bi061749a
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发表时间：
2007-02-20
期刊：
影响因子：
2.9
通讯作者：
Fink, Anthony L.
中科院分区：
文献类型：
--
作者：
Martinez, Zak;Zhu, Min;Fink, Anthony L.
α-突触核蛋白的聚集被认为是帕金森病病因学中的关键步骤。α-突触核蛋白存在于胞质溶胶中，与神经元突触前区域的膜相关，最近报道与脂筏和小窝相关。我们研究了几种脑鞘脂和α-突触核蛋白之间的相互作用，发现α-突触核蛋白特异性结合含有神经节苷脂GM 1的小单层囊泡（SUV）。这导致大量α-螺旋结构的诱导和α-突触核蛋白原纤维形成的抑制或消除，这取决于存在的GM 1的量。含有全脑神经节苷脂、神经节苷脂GM 2或GM 3或去唾液酸GM 1的SUV对α-突触核蛋白纤维化具有弱抑制作用，并诱导一些α-螺旋结构，而研究的所有其他鞘脂与α-突触核蛋白的相互作用可忽略不计。α-突触核蛋白与含有GM 1的SUV的结合伴随着α-突触核蛋白的寡聚体的形成。家族性突变体A53 T α-突触核蛋白以与野生型类似的方式与含有GM 1的SUV相互作用，而A30 P突变体显示出最小的相互作用。这是第一个详细的报告显示GM 1和α-突触核蛋白之间的直接关联，这是由于螺旋α-突触核蛋白和GM 1的唾液酸和碳水化合物部分之间的特异性相互作用。α-突触核蛋白的招聘GM 1小窝和脂筏地区的膜可以解释α-突触核蛋白的本地化突触前膜和提出的可能性，干扰GM 1/筏协会可能会引起的变化，有助于PD的发病机制的α-突触核蛋白。
The aggregation of alpha-synuclein is believed to be a key step in the etiology of Parkinson's disease. alpha-Synuclein is found in the cytosol and is associated with membranes in the presynaptic region of neurons and has recently been reported to be associated with lipid rafts and caveolae. We examined the interactions between several brain sphingolipids and alpha-synuclein and found that alpha-synuclein specifically binds to ganglioside GM1-containing small unilamellar vesicles (SUVs). This results in the induction of substantial alpha-helical structure and inhibition or elimination of alpha-synuclein fibril formation, depending on the amount of GM1 present. SUVs containing total brain gangliosides, gangliosides GM2 or GM3, or asialo-GM1 had weak inhibitory effects on alpha-synuclein fibrillation and induced some alpha-helical structure, while all other sphingolipids studied showed negligible interaction with alpha-synuclein. alpha-Synuclein binding to GM1-containing SUVs was accompanied by formation of oligomers of alpha-synuclein. The familial mutant A53T alpha-synuclein interacted with GM1-containing SUVs in an analogous manner to wild type, whereas the A30P mutant showed minimal interaction. This is the first detailed report showing a direct association between GM1 and alpha-synuclein, which is attributed to specific interaction between helical alpha-synuclein and both the sialic acid and carbohydrate moieties of GM1. The recruitment of alpha-synuclein by GM1 to caveolae and lipid raft regions in membranes could explain alpha-synuclein's localization to presynaptic membranes and raises the possibility that perturbation of GM1/raft association could induce changes in alpha-synuclein that contribute to the pathogenesis of PD.