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首页> 外文期刊>Biochemistry >Lipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization
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Lipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization

机译：脂质膜影响小分子抑制亨廷顿纤维化的能力

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摘要

Several diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease (HD), are associated with specific proteins aggregating and depositing within tissues and/or cellular compartments. The aggregation of these proteins is characterized by the formation of extended, beta-sheet rich fibrils, termed amyloid. In addition, a variety of other aggregate species also form, including oligomers and protofibrils. Specifically, HD is caused by the aggregation of the huntingtin (htt) protein that contains an expanded polyglutamine domain. Due to the link between protein aggregation and disease, small molecule aggregation inhibitors have been pursued as potential therapeutic agents. Two such small molecules are epigallocatechin 3-gallate (EGCG) and curcumin, both of which inhibit the fibril formation of several amyloid-forming proteins. However, amyloid formation is a complex process that is strongly influenced by the protein's environment, leading to distinct aggregation pathways. Thus, changes in the protein's environment may alter the effectiveness of aggregation inhibitors. A well-known modulator of amyloid formation is lipid membranes. Here, we investigated if the presence of lipid vesicles altered the ability of EGCG or curcumin to modulate htt aggregation and influence the interaction of htt with lipid membranes. The presence of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine or total brain lipid extract vesicles prevented the curcumin from inhibiting htt fibril formation. In contrast, EGCG's inhibition of htt fibril formation persisted in the presence of lipids. Collectively, these results highlight the complexity of htt aggregation and demonstrate that the presence of lipid membranes is a key modifier of the ability of small molecules to inhibit htt fibril formation.
机译：几种疾病，包括阿尔茨海默病，帕金森病和亨廷顿疾病（HD），与组织和/或细胞室内的特异性蛋白质相关联。这些蛋白质的聚集的特征在于形成延长，β-片状的原纤维，称为淀粉样蛋白。此外，各种其他骨料物种也形成，包括低聚物和原生纤维。具体地，HD是由含有膨胀聚谷氨酰胺结构域的亨廷特汀（HTT）蛋白的聚集引起的。由于蛋白质聚集和疾病之间的联系，已经追求了小分子聚集抑制剂作为潜在的治疗剂。两种这样的小分子是EpigallocateChin 3-gallate（egcg）和姜黄素，其两者均抑制几种淀粉样蛋白的纤维状形成蛋白质。然而，淀粉样蛋白形成是一种复杂的方法，受蛋白质的环境受到强烈影响，导致不同的聚集途径。因此，蛋白质环境的变化可能改变聚集抑制剂的有效性。淀粉样蛋白形成的着名调节剂是脂质膜。在这里，我们研究了脂质囊泡的存在改变了EGCG或姜黄素调节HTT聚集并影响HTT与脂质膜的相互作用的能力。 1-palmItoyl-2-Oleyoyl-甘油-3-磷光籽或总脑脂质提取囊泡的存在阻止了姜黄素抑制HTT原纤维形成。相反，EGCG在脂质存在下持续存在HTT原纤维形成。总的来说，这些结果突出了HTT聚集的复杂性，并证明了脂膜的存在是小分子抑制HTT原纤维形成的能力的关键改性剂。

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  • 来源
    《Biochemistry》 |2019年第43期|共13页
  • 作者

    Beasley Maryssa; Stonebraker Alyssa R.; Hasan Iraj; Kapp Kathryn L.; Liang Barry J.; Agarwal Garima; Groover Sharon; Sedighi Faezeh; Legleiter Justin;

  • 作者单位

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

    West Virginia Univ C Eugene Bennett Dept Chem 217 Clark Hall Morgantown WV 26506 USA;

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  • 正文语种 eng
  • 中图分类 生物化学;
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