Center for Neuroscience and Cell Biology & Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
Prog Neurobiol. 2011 Sep 15;95(1):26-48. doi: 10.1016/j.pneurobio.2011.06.007. Epub 2011 Jun 28.
Polyglutamine (polyQ) diseases are a group of nine neurodegenerative disorders caused by an unstable CAG expansion in the codifying region of their respective associated genes. However, each polyQ disease displays a different symptomatic and pathoanatomic profile and the proteins involved share no homology outside the polyQ tract. This suggests that the other regions of the proteins and the cellular functions they mediate are important in defining disease progression and specificity. Machado-Joseph disease (MJD), the most common form of spinocerebellar ataxia worldwide, is a progressive and ultimately fatal neurodegenerative disorder caused by polyQ expansion in ataxin-3 (atx3), a conserved and ubiquitous protein known to bind polyubiquitin chains and to function as a deubiquitinating enzyme. Atx3 has been linked to protein homeostasis maintenance, transcription, cytoskeleton regulation and myogenesis, but its precise biologic function remains a mystery, limiting the understanding of the mechanisms by which the mutated protein leads to the selective neuronal death profile observed in MJD patients. A number of recent evidence support the idea that the toxic entities behind neuronal demise may be either the dysfunctional expanded atx3 or the soluble amyloid-like oligomers formed by self-assembly of the aggregation-prone mutated protein. Expanded atx3 pathogenicity is likely the result of a series of events implicating both atx3 dysfunction and aggregation, possibly involving both full-length atx3 and polyQ-containing fragments that may act as seeds for protein aggregation. A deeper understanding of polyQ protein biology, the way the expansion alters their features, and the consequences of these changes for cell functioning and survival are sure to be of critical importance for developing future treatment of polyQ diseases.
多聚谷氨酰胺（polyQ）疾病是一组由编码区域不稳定 CAG 扩展引起的 9 种神经退行性疾病。然而，每种多聚谷氨酰胺疾病都表现出不同的症状和病理解剖特征，并且涉及的蛋白质在聚谷氨酰胺区域之外没有同源性。这表明蛋白质的其他区域和它们介导的细胞功能对于定义疾病进展和特异性很重要。马查多-约瑟夫病（MJD）是全球最常见的脊髓小脑共济失调形式，是一种进行性的、最终致命的神经退行性疾病，由 ataxin-3（atx3）中的 polyQ 扩展引起，ataxin-3 是一种保守且普遍存在的蛋白质，已知能结合多泛素链并作为去泛素化酶发挥作用。Atx3 与蛋白质稳态维持、转录、细胞骨架调节和肌发生有关，但它的确切生物学功能仍然是一个谜，限制了对突变蛋白导致 MJD 患者中观察到的选择性神经元死亡模式的机制的理解。最近有许多证据支持这样一种观点，即神经元死亡背后的毒性实体可能是功能失调的扩展 atx3 或由易于聚集的突变蛋白自组装形成的可溶性淀粉样寡聚物。扩展 atx3 的致病性可能是一系列事件的结果，这些事件同时涉及 atx3 功能障碍和聚集，可能涉及全长 atx3 和可能作为蛋白质聚集种子的聚谷氨酰胺片段。深入了解多聚谷氨酰胺蛋白生物学、扩展如何改变它们的特征，以及这些变化对细胞功能和存活的影响，对于开发未来的多聚谷氨酰胺疾病治疗方法肯定至关重要。
