Regulation of the structural dynamics, aggregation, and pathogenicity of polyQ-expanded Huntingtin by osmolytes.

3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology
Alice Y Liu, Amala Mathew, Christopher Karim, Pierre Eshak, Kuang Yu Chen
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引用次数: 0

Abstract

Huntington Disease is an autosomal dominant neurodegenerative disease caused by expansion of the polymorphic trinucleotide CAG repeat of the HTT gene to code for an expanded glutamine track of the mutant Huntingtin protein (mHTT). Like other neurodegenerative diseases, symptomatic presentation of Huntington Disease is age-dependent or age-related. This age-dependent manifestation of an autosomal dominant disease trait underscores important and possibly priming role of age-related changes in cellular physiology that are conducive to disease presentation. Herein, we present studies on the effects of osmolytes on mHTT structuring and aggregation, vis-a-vis pathogenicity. We show that stabilizing polyol osmolytes, by their generic activity in promoting protein structuring and compaction, drive aggregation of the disordered mHTT protein and simultaneously inhibit their binding to and sequestration of key transcription factors for improved homeostasis and cell survival under stress. These and related observations in the literature give strong support to the notion that lower molecular weight and structurally dynamic forms of mHTT contribute importantly to disease pathogenesis. Aging is associated with important changes in the cell environment-disease protein accumulation, reduced hydration, and macromolecular crowding as examples. These changes have significant consequences on the structuring and pathogenicity of the disordered mHTT protein. A crowded and less hydrated aging cell environment is conducive to mHTT binding to and inhibition of cell regulatory protein function on the one hand, and in promoting mHTT aggregation on the other hand, to culminate in Huntington disease presentation.

渗透菌对聚q扩展亨廷顿蛋白结构动力学、聚集和致病性的调控。
亨廷顿病是一种常染色体显性神经退行性疾病,由HTT基因的多态三核苷酸CAG重复扩增引起,该重复扩增编码突变亨廷顿蛋白(mHTT)的谷氨酰胺轨道。像其他神经退行性疾病一样,亨廷顿病的症状表现与年龄有关。这种常染色体显性疾病特征的年龄依赖性表现强调了细胞生理学中有利于疾病表现的年龄相关变化的重要和可能的启动作用。在此,我们介绍了渗透物对mHTT结构和聚集的影响,以及对致病性的影响。我们发现,稳定多元醇渗透物通过其促进蛋白质结构和压实的一般活性,驱动紊乱的mHTT蛋白聚集,同时抑制其与关键转录因子的结合和隔离,从而改善体内平衡和应激下的细胞存活。这些以及文献中的相关观察结果有力地支持了mHTT的低分子量和结构动态形式在疾病发病机制中起重要作用的观点。衰老与细胞环境的重要变化有关,如蛋白质积累、水合作用减少和大分子拥挤。这些变化对紊乱的mHTT蛋白的结构和致病性有重要影响。拥挤和缺水的衰老细胞环境一方面有利于mHTT结合和抑制细胞调节蛋白功能,另一方面促进mHTT聚集,最终导致亨廷顿病的出现。
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来源期刊
CiteScore
5.00
自引率
0.00%
发文量
110
审稿时长
4-8 weeks
期刊介绍: Progress in Molecular Biology and Translational Science (PMBTS) provides in-depth reviews on topics of exceptional scientific importance. If today you read an Article or Letter in Nature or a Research Article or Report in Science reporting findings of exceptional importance, you likely will find comprehensive coverage of that research area in a future PMBTS volume.
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