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首页> 外文期刊>Neuromolecular medicine >Deciphering the roles of trehalose and Hsp104 in the inhibition of aggregation of mutant huntingtin in a yeast model of Huntington's disease
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Deciphering the roles of trehalose and Hsp104 in the inhibition of aggregation of mutant huntingtin in a yeast model of Huntington's disease

机译：解读海藻糖和Hsp104在亨廷顿氏病酵母模型中抑制突变型亨廷顿蛋白聚集的作用

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摘要

Despite the significant amount of experimental data available on trehalose, the molecular mechanism responsible for its intracellular stabilising properties has not emerged yet. The repair of cellular homeostasis in many protein-misfolding diseases by trehalose is credited to the disaccharide being an inducer of autophagy, a mechanism by which aggregates of misfolded proteins are cleared by the cell. In this work, we expressed the pathogenic N-terminal fragment of huntingtin in Δnth1 mutant (unable to degrade trehalose) of Saccharomyces cerevisiae BY4742 strain. We show that the presence of trehalose resulted in the partitioning of the mutant huntingtin in the soluble fraction of the cell. This led to reduced oxidative stress and improved cell survival. The beneficial effect was independent of the expression of the major cellular antioxidant enzyme, superoxide dismutase. Additionally, trehalose led to the overexpression of the heat shock protein, Hsp104p, in mutant huntingtin-expressing cells, and resulted in rescue of the endocytotic defect in the yeast cell. We propose that at least in the initial stages of aggregation, trehalose functions as a stabiliser, increasing the level of monomeric mutant huntingtin protein, with its concomitant beneficial effects, in addition to its role as an inducer of autophagy.
机译：尽管有关海藻糖的大量实验数据可用，但尚未发现负责其细胞内稳定特性的分子机制。海藻糖在许多蛋白质错配疾病中修复细胞稳态的作用归因于二糖，它是自噬的诱导剂，通过这种机制，错折叠的蛋白质聚集体被细胞清除。在这项工作中，我们在啤酒酵母BY4742菌株的Δnth1突变体（无法降解海藻糖）中表达了亨廷顿蛋白的致病性N末端片段。我们显示，海藻糖的存在导致突变的亨廷顿蛋白在细胞的可溶性部分中的分配。这导致减少的氧化应激和改善的细胞存活。有益作用与主要细胞抗氧化酶超氧化物歧化酶的表达无关。另外，海藻糖导致表达突变的亨廷顿蛋白的细胞中热休克蛋白Hsp104p的过表达，并导致酵母细胞中内吞缺陷的挽救。我们建议至少在聚集的初始阶段，海藻糖起稳定剂的作用，增加单体突变型亨廷顿蛋白的水平，并伴随其有益的作用，此外还起自噬的诱导作用。

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