University Medical Center Groningen, Department of Cell Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Int J Biochem Cell Biol. 2012 Oct;44(10):1657-69. doi: 10.1016/j.biocel.2012.03.011. Epub 2012 Mar 28.
A number of neurological and muscular disorders are characterized by the accumulation of aggregate-prone proteins and are referred to as protein deposit or protein conformation diseases. Besides some sporadic forms, most of them are genetically inherited in an autosomal dominant manner, although recessive forms also exist. Although genetically very heterogeneous, some of these diseases are the result of mutations in some members of the mammalian small heat shock protein family (sHSP/HSPB), which are key players of the protein quality control system and participate, together with other molecular chaperones and co-chaperones, in the maintenance of protein homeostasis. Thus, on one hand upregulation of specific members of the HSPB family can exert protective effects in protein deposit diseases, such as the polyglutamine diseases. On the other hand, mutations in the HSPBs lead to neurological and muscular disorders, which may be due to a loss-of-function in protein quality control and/or to a gain-of-toxic function, resulting from the aggregation-proneness of the mutants. In this review we summarize the current knowledge about some of the best characterized functions of the HSPBs (e.g. role in cytoskeleton stabilization, chaperone function, anti-aggregation and anti-apoptotic activities), also highlighting differences in the properties of the various HSPBs and how these may counteract protein aggregation diseases. We also describe the mutations in the various HSPBs associated with neurological and muscular disorders and we discuss how gain-of-toxic function mechanisms (e.g. due to the mutated HSPB protein instability and aggregation) and/or loss-of-function mechanisms can contribute to HSPB-associated pathologies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.
许多神经和肌肉疾病的特征是聚集倾向蛋白的积累，因此被称为蛋白沉积或蛋白构象疾病。除了一些散发性形式外，大多数疾病以常染色体显性遗传方式遗传，尽管也存在隐性形式。尽管在遗传上非常多样化，但这些疾病中的一些是哺乳动物小分子热休克蛋白家族（sHSP/HSPB）的某些成员发生突变的结果，这些成员是蛋白质量控制系统的关键参与者，与其他分子伴侣和共伴侣一起参与维持蛋白平衡。因此，一方面，小分子热休克蛋白家族特定成员的上调可以在蛋白沉积疾病（如多聚谷氨酰胺疾病）中发挥保护作用。另一方面，HSPB 的突变导致神经和肌肉疾病，这可能是由于蛋白质量控制的功能丧失和/或由于突变体的聚集倾向导致的毒性功能获得。在这篇综述中，我们总结了目前关于 HSPB 的一些特征功能的知识（例如在细胞骨架稳定、伴侣功能、抗聚集和抗细胞凋亡活性方面的作用），还强调了各种 HSPB 的特性差异，以及这些差异如何对抗蛋白聚集疾病。我们还描述了与神经和肌肉疾病相关的各种 HSPB 的突变，并讨论了毒性功能获得机制（例如由于突变 HSPB 蛋白的不稳定性和聚集）和/或功能丧失机制如何导致 HSPB 相关病理。本文是题为“小分子热休克蛋白在生理和病理中的作用”的专刊的一部分。
