The C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, West Virginia 26506, United States.
Department of Ophthalmology, West Virginia University, Morgantown, West Virginia 26506, United States.
Biochemistry. 2020 Dec 15;59(49):4681-4693. doi: 10.1021/acs.biochem.0c00788. Epub 2020 Nov 30.
Huntington's disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of a polyglutamine (polyQ) tract in the first exon of the htt protein (htt). PolyQ expansion triggers the aggregation of htt into a variety of structures, including oligomers and fibrils. This aggregation is impacted by the first 17 N-terminal amino acids (Nt17) of htt that directly precedes the polyQ domain. Beyond impacting aggregation, Nt17 associates with lipid membranes by forming an amphipathic α-helix. Post-translational modifications within Nt17 are known to modify HD pathology, and in particular, phosphorylation at T3, S13, and/or S16 retards fibrillization and ameliorates the phenotype in HD models. Due to Nt17's propensity to interact with lipid membranes, the impact of introducing phosphomimetic mutations (T3D, S13D, and S16D) into htt-exon1 on aggregation in the presence of a variety of model lipid membranes (total brain lipid extract, 1-palmitoyl-2-oleoyl-glycero-3-phosphatidylcholine, and 1-palmitoyl-2-oleoyl--glycero-3-phospho-1'--glycerol) was investigated. Phosphomimetic mutations altered htt's interaction with and aggregation in the presence of lipids; however, this was dependent on the lipid system.
亨廷顿病（HD）是一种神经退行性疾病，由 htt 蛋白（htt）第一外显子中异常扩展的多聚谷氨酰胺（polyQ）序列引起。polyQ 扩展触发 htt 聚集形成多种结构，包括寡聚体和纤维。这种聚集受到 htt 前 17 个 N 端氨基酸（Nt17）的影响，这些氨基酸直接位于 polyQ 结构域之前。除了影响聚集外，Nt17 通过形成两亲性α螺旋与脂质膜结合。已知 Nt17 内的翻译后修饰会改变 HD 病理学，特别是 T3、S13 和/或 S16 的磷酸化会减缓纤维形成并改善 HD 模型中的表型。由于 Nt17 倾向于与脂质膜相互作用，因此研究了在各种模型脂质膜（全脑脂质提取物、1-棕榈酰-2-油酰甘油-3-磷酸胆碱和 1-棕榈酰-2-油酰甘油-3-磷酸-1'-甘油）存在的情况下，将磷酸模拟突变（T3D、S13D 和 S16D）引入 htt-exon1 对聚集的影响。磷酸模拟突变改变了 htt 在脂质存在下的相互作用和聚集；然而，这取决于脂质系统。
