Department of Biochemistry, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24-25, 14467 Potsdam, Germany.
Biochemistry. 2011 Mar 29;50(12):2048-60. doi: 10.1021/bi1018368. Epub 2011 Feb 20.
In response to stress small organic compounds termed osmolytes are ubiquitously accumulated in all cell types to regulate the intracellular solvent quality and to counteract the deleterious effect on the stability and function of cellular proteins. Given the evidence that destabilization of the native state of a protein either by mutation or by environmental changes triggers the aggregation in the neurodegenerative pathologies, the modulation of the intracellular solute composition with osmolytes is an attractive strategy to stabilize an aggregating protein. Here we report the effect of three natural osmolytes on the in vivo and in vitro aggregation landscape of huntingtin exon 1 implicated in the Huntington's disease. Trimethylamine N-oxide (TMAO) and proline redirect amyloid fibrillogenesis of the pathological huntingtin exon 1 to nonamyloidogenic amorphous assemblies via two dissimilar molecular mechanisms. TMAO causes a rapid formation of bulky amorphous aggregates with minimally exposed surface area, whereas proline solubilizes the monomer and suppresses the accumulation of early transient aggregates. Conversely, glycine-betaine enhances fibrillization in a fashion reminiscent of the genesis of functional amyloids. Strikingly, none of the natural osmolytes can completely abrogate the aggregate formation; however, they redirect the amyloidogenesis into alternative, nontoxic aggregate species. Our study reveals new insights into the complex interactions of osmoprotectants with polyQ aggregates.
为应对压力，所有细胞类型中都会普遍积累称为渗透物的小型有机化合物，以调节细胞内溶剂质量，并抵消对细胞蛋白稳定性和功能的有害影响。鉴于证据表明，蛋白质天然状态的不稳定性无论是由突变还是环境变化引起，都会触发神经退行性病变中的聚集，因此用渗透物调节细胞内溶质组成是稳定聚集蛋白的一种有吸引力的策略。在这里，我们报告了三种天然渗透物对涉及亨廷顿病的 huntingtin 外显子 1 的体内和体外聚集状态的影响。三甲胺 N-氧化物 (TMAO) 和脯氨酸通过两种不同的分子机制将病理性 huntingtin 外显子 1 的淀粉样纤维形成重定向为非淀粉样的无定形组装。TMAO 导致快速形成具有最小暴露表面积的大而无定形的聚集体，而脯氨酸则使单体溶解并抑制早期瞬态聚集体的积累。相反，甘氨酸甜菜碱以类似于功能性淀粉样蛋白生成的方式增强纤维形成。引人注目的是，没有一种天然渗透物可以完全阻止聚集体的形成；然而，它们将淀粉样变重定向为替代的、无毒的聚集体。我们的研究揭示了渗透物与聚 Q 聚集体之间复杂相互作用的新见解。
