GM1 Cluster Mediates Formation of Toxic A尾 Fibrils by Providing Hydrophobic Environments

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• 作者：Saori Fukunaga ; Hiroshi Ueno ; Takahiro Yamaguchi ; Yoshiaki Yano ; Masaru Hoshino ; Katsumi Matsuzaki
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：October 16, 2012
• 年：2012
• 卷：51
• 期：41
• 页码：8125-8131
• 全文大小：266K
• 年卷期：v.51,no.41(October 16, 2012)
• ISSN：1520-4995

文摘

The conversion of soluble, nontoxic amyloid 尾-proteins (A尾) to aggregated, toxic forms rich in 尾-sheets is considered to be a key step in the development of Alzheimer鈥檚 disease. Accumulating evidence suggests that lipid鈥損rotein interactions play a crucial role in the aggregation of amyloidogenic proteins like A尾. Our group has previously reported that amyloid fibrils of A尾 formed on membranes containing clusters of GM1 ganglioside (M-fibrils) exhibit greater cytotoxicity than fibrils formed in aqueous solution (W-fibrils) [Okada (2008) J. Mol. Biol.382, 1066鈭?074]. W-fibrils are considered to consist of in-register parallel 尾-sheets. However, the precise molecular structure of M-fibrils and force driving the formation of toxic fibrils remain unclear. In this study, we hypothesized that low-polarity environments provided by GM1 clusters drive the formation of toxic fibrils and compared the structure and cytotoxicity of W-fibrils, M-fibrils, and aggregates formed in a low-polarity solution mimicking membrane environments. First, we determined solvent conditions which mimic the polarity of raftlike membranes using A尾-(1鈥?0) labeled with the 7-diethylaminocoumarin-3-carbonyl dye. The polarity of a mixture of 80% 1,4-dioxane and 20% water (v/v) was found to be close to that of raftlike membranes. A尾-(1鈥?0) formed amyloid fibrils within several hours in 80% dioxane (D-fibrils) or in the presence of raftlike membranes, whereas a much longer incubation time was required for fibril formation in a conventional buffer. D-fibrils were morphologically similar to M-fibrils. Fourier-transform infrared spectroscopy suggested that M-fibrils and D-fibrils contained antiparallel 尾-sheets. These fibrils had greater surface hydrophobicity and exhibited significant toxicity against human neuroblastoma SH-SY5Y cells, whereas W-fibrils with less surface hydrophobicity were not cytotoxic. We concluded that ganglioside clusters mediate the formation of toxic amyloid fibrils of A尾 with an antiparallel 尾-sheet structure by providing less polar environments.