Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes.
Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes.
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DOI：
10.1021/acsomega.7b01472
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发表时间：
2018-01-31
期刊：
影响因子：
4.1
通讯作者：
Legleiter J
中科院分区：
文献类型：
--
作者：
Chaibva M;Gao X;Jain P;Campbell WA 4th;Frey SL;Legleiter J
亨廷顿病（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白（htt） n端附近的聚谷氨酰胺（polyQ）束扩张超过临界阈值引起。扩展的polyQ促进各种htt寡聚物和纤维聚集体的形成，这些聚集体积聚成HD相关的标志性蛋白包涵体。HTT还与含有多种脂质的许多细胞膜和亚细胞膜高度相关。由于在HD患者中观察到脂质稳态和代谢异常，我们研究了鞘磷脂（SM）和神经节苷脂（GM1）含量的变化如何改变htt和脂质膜之间的相互作用。HD患者的SM成分发生改变，GM1在HD动物模型中显示出保护作用。结合Langmuir单层通道技术、囊泡渗透性和结合试验以及原位原子力显微镜（AFM），直接监测模型、合成htt肽和全长htt-exon1重组蛋白与由总脑脂提取物（TBLE）和不同量外源添加的SM或GM1组成的模型膜的相互作用。添加SM或GM1均可减少htt插入脂质单层。然而，SM含量增加的table囊泡更容易受到高温诱导的渗透作用，而GM1对渗透作用没有影响。纯表双分子层和富含GM1的表双分子层在暴露于http -exon1后形成了粗糙的颗粒状区域，而富含SM的表双分子层则形成了表面光滑的高原状结构域。无论诱导形态如何，在所有双层体系中均观察到寡聚物聚集。总的来说，这些观察结果表明，脂质组成及其对膜材料性能的后续影响强烈地影响了htt在脂质膜上的结合和聚集。
Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt and lipid membranes. SM composition is altered in HD, and GM1 has been shown to have protective effects in animal models of HD. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy (AFM) were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added SM or GM1. The addition of either SM or GM1 decreased htt insertion into the lipid monolayers. However, TBLE vesicles with an increased SM content were more susceptible to htt-induced permeabilization, whereas GM1 had no effect on permeablization. Pure TBLE bilayers and TBLE bilayers enriched with GM1 developed regions of roughened, granular morphologies upon exposure to htt-exon1, but plateau-like domains with a smoother appearance formed in bilayers enriched with SM. Oligomeric aggregates were observed on all bilayer systems regardless of induced morphology. Collectively, these observations suggest that the lipid composition and its subsequent effects on membrane material properties strongly influence htt binding and aggregation on lipid membranes.
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