The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States.
Rockefeller Neurosciences Institute , West Virginia University , 1 Medical Center Drive , P.O. Box 9303, Morgantown , West Virginia 26505 , United States.
Biochemistry. 2019 Oct 29;58(43):4361-4373. doi: 10.1021/acs.biochem.9b00739. Epub 2019 Oct 17.
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, β-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.
几种疾病，包括阿尔茨海默病、帕金森病和亨廷顿病（HD），都与特定蛋白质在组织和/或细胞区室中聚集和沉积有关。这些蛋白质的聚集特征是形成扩展的、富含β-折叠的纤维，称为淀粉样蛋白。此外，还形成了各种其他聚集物，包括寡聚物和原纤维。具体而言，HD 是由含有扩展多聚谷氨酰胺结构域的亨廷顿（htt）蛋白的聚集引起的。由于蛋白质聚集与疾病之间存在联系，因此小分子聚集抑制剂已被作为潜在的治疗剂进行研究。两种这样的小分子是表没食子儿茶素没食子酸酯（EGCG）和姜黄素，它们都能抑制几种形成淀粉样蛋白的蛋白质的纤维形成。然而，淀粉样蛋白的形成是一个复杂的过程，强烈受到蛋白质环境的影响，导致不同的聚集途径。因此，蛋白质环境的变化可能会改变聚集抑制剂的效果。众所周知的淀粉样蛋白形成调节剂是脂质膜。在这里，我们研究了脂质囊泡的存在是否改变了 EGCG 或姜黄素调节 htt 聚集的能力，并影响 htt 与脂质膜的相互作用。1-棕榈酰-2-油酰基-甘油-3-磷酸胆碱或总脑脂质提取物囊泡的存在阻止了姜黄素抑制 htt 纤维形成。相比之下，脂质存在时，EGCG 抑制 htt 纤维形成的能力仍然存在。总的来说，这些结果突出了 htt 聚集的复杂性，并表明脂质膜的存在是小分子抑制 htt 纤维形成能力的关键调节剂。
