Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Curr Med Chem. 2010;17(27):3058-68. doi: 10.2174/092986710791959800.
Protein aggregation is a key mechanism involved in neurodegeneration associated with Alzheimer's, Parkinson's and Huntington's diseases. Nine diseases (including Huntington's) arise from polyglutamine (polyQ) expansion above a repeat threshold of approximately 37 glutamines, and neuronal toxicity correlates with the process of protein aggregation. The similar toxic gain-of-function mechanism of the nine diseases supports the hypothesis that disease onset and progression is dependent upon polyQ expansion. However, there is an increasing body of literature demonstrating that the protein context of the polyQ tract has an essential role in the disease process. The composition of regions flanking repeats can alter the biochemical and biophysical properties of the polyQ region. A number of the disease proteins are proteolytically cleaved, with release of the polyQ-containing fragment initiating aggregation. Interactions of flanking domains with other molecules can also influence aggregation and cellular localization, which are critical factors for toxicity. More recently, there is evidence that domains flanking the polyQ tract can also aggregate independent of the polyQ tract, and that this significantly alters the rate at which the polyQ regions form fibrillar aggregates and the properties of these aggregates. In this review we consider the role of protein context in modulating the polyQ diseases and the therapeutic potential of targeting non-polyQ protein properties.
蛋白质聚集是与阿尔茨海默病、帕金森病和亨廷顿病相关的神经退行性变的关键机制。有九种疾病（包括亨廷顿病）是由于聚谷氨酰胺（polyQ）扩展超过大约 37 个谷氨酰胺的重复阈值而引起的，神经元毒性与蛋白质聚集的过程相关。这九种疾病具有相似的毒性获得功能机制，支持疾病发作和进展依赖于 polyQ 扩展的假说。然而，越来越多的文献表明，polyQ 区域的蛋白质背景在疾病过程中起着至关重要的作用。重复区域侧翼的区域组成可以改变 polyQ 区域的生化和生物物理特性。许多疾病蛋白被蛋白水解切割，释放含有 polyQ 的片段会引发聚集。侧翼结构域与其他分子的相互作用也会影响聚集和细胞定位，这是毒性的关键因素。最近有证据表明，polyQ 区域侧翼的结构域也可以独立于 polyQ 区域发生聚集，这显著改变了 polyQ 区域形成纤维状聚集物的速度以及这些聚集物的特性。在这篇综述中，我们考虑了蛋白质背景在调节 polyQ 疾病中的作用以及针对非 polyQ 蛋白特性的治疗潜力。
