Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK.
Acta Neuropathol. 2010 Oct;120(4):419-37. doi: 10.1007/s00401-010-0703-0. Epub 2010 Jun 1.
Polyglutamine (polyQ) diseases are associated with a CAG/polyQ expansion mutation in unrelated proteins. Upon elongation of the glutamine tract, disease proteins aggregate within cells, mainly in the central nervous system (CNS) and this aggregation process is associated with neurotoxicity. However, it remains unclear to what extent and how this aggregation causes neuronal dysfunction in the CNS. Aiming at preventing neuronal dysfunction, it will be crucial to determine the links between aggregation and cellular dysfunction, understand the folding pathway of polyQ proteins and discover the relative neurotoxicity of polyQ protein species formed along the aggregation pathway. Here, we review what is known about conformations of polyQ peptides and proteins in their monomeric state from experimental and modelling data, how conformational changes of polyQ proteins relate to their oligomerisation and morphology of aggregates and which cellular function are impaired by oligomers, in vitro and in vivo. We also summarise the key modulatory cellular mechanisms and co-factors, which could affect the folding pathway and kinetics of polyQ aggregation. Although many studies have investigated the relationship between polyQ aggregation and toxicity, these have mainly focussed on investigating changes in the formation of the classical hallmark of polyQ diseases, i.e. microscopically visible inclusion bodies. However, recent studies in which oligomeric species have been considered start to shed light on the identity of neurotoxic oligomeric species. Initial evidence suggests that conformational changes induced by polyQ expansions and their surrounding sequence lead to the formation of particular oligomeric intermediates that may differentially affect neurotoxicity.
多聚谷氨酰胺（polyQ）疾病与无关联蛋白中的 CAG/polyQ 扩展突变有关。当谷氨酰胺链延长时，疾病蛋白在细胞内聚集，主要在中枢神经系统（CNS）中，并且这个聚集过程与神经毒性有关。然而，目前尚不清楚这种聚集在多大程度上以及如何导致中枢神经系统中的神经元功能障碍。为了防止神经元功能障碍，确定聚集和细胞功能障碍之间的联系，了解 polyQ 蛋白的折叠途径以及发现沿着聚集途径形成的相对神经毒性的 polyQ 蛋白种类，将是至关重要的。在这里，我们回顾了从实验和建模数据中了解到的单体状态下 polyQ 肽和蛋白的构象，polyQ 蛋白构象变化如何与其寡聚化和聚集体形态相关，以及寡聚体在体外和体内损害了哪些细胞功能。我们还总结了关键的调节细胞机制和共因子，这些机制可能影响 polyQ 聚集的折叠途径和动力学。尽管许多研究已经调查了 polyQ 聚集和毒性之间的关系，但这些研究主要集中在研究经典 polyQ 疾病标志的形成变化上，即显微镜可见的包涵体。然而，最近考虑寡聚体种类的研究开始揭示神经毒性寡聚体种类的特征。初步证据表明，polyQ 扩展及其周围序列诱导的构象变化导致形成特定的寡聚中间体，这些中间体可能会对神经毒性产生不同的影响。
