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首页> 外文期刊>Biochemistry >Natural Osmolytes Remodel the Aggregation Pathway of Mutant Huntingtin Exon 1
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Natural Osmolytes Remodel the Aggregation Pathway of Mutant Huntingtin Exon 1

机译：天然渗透物改造突变亨廷顿外显子1的聚集途径

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摘要

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.
机译：响应于应力小有机化合物，称为Osmolytes普遍存在所有细胞类型中以调节细胞内溶剂质量并抵消对细胞蛋白质的稳定性和功能的有害影响。鉴于通过突变或环境变化造成蛋白质的天然状态的证据触发了神经变性病理学中的聚集，细胞内溶质组合物与渗透物的调节是稳定聚集蛋白的有吸引力的策略。在这里，我们举报了三种天然渗透物对亨廷顿疾病的体内和体外聚集景观的影响。三甲胺N-氧化物（TMAO）和脯氨酸通过两种异种分子机制将病理亨廷顿外显子1的淀粉样蛋白原纤维发生。 TMAO导致庞大的无定形聚集体快速形成，具有最小暴露的表面积，而脯氨酸溶解单体并抑制早期瞬时聚集体的积累。相反，甘氨酸 - 甜菜碱以时尚的增强原纤化，使官能淀粉样蛋白的成因同时发生。令人惊讶的是，没有一种天然的渗透物可以完全消除骨料形成;然而，它们将淀粉样催化剂重定向到替代的无毒聚集物种中。我们的研究揭示了新的洞察力与PolyQ聚集体的复杂相互作用。

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  • 来源
    《Biochemistry》 |2011年第12期|共13页
  • 作者

    Tejas Borwankar; Christoph Rothlein; Gong Zhang; Anne Techen; Carsten Dosche; Zoya Ignatova;

  • 作者单位

    Department of Biochemistry Institute of Biochemistry and Biology Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

    Department of Biochemistry Institute of Biochemistry and Biology Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

    Department of Biochemistry Institute of Biochemistry and Biology Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

    Department of Physical Chemistry Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

    Department of Physical Chemistry Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

    Department of Biochemistry Institute of Biochemistry and Biology Insitute of Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14467 Potsdam Germany;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Osmolytes; Aggregation; Mutant;

    机译：osmolytes;聚集;突变体;

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