Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Curr Pharm Biotechnol. 2010 Feb;11(2):180-7. doi: 10.2174/138920110790909740.
The homeostasis of the protein synthesis and degradation is crucial for cell survival. Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. The principal routes of intracellular protein metabolism are the ubiquitin proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They collaborate to degrade wasted proteins and interact each other to cope with the pathological conditions, in which molecular chaperones play collective roles by assisting the protein targeting to the proteasome or autophagy. It is known that intracellular protein degradation functions are decreased with aging in many tissues and organs. Failure to perform their functions could underlie the inability of cells to adapt to stress conditions, lead to accelerated course of misfolding protein deposit and the inclusion body formation, and eventually result in neurodegeneration.One of the functions of the molecular chaperones is to help the new synthesized or the misfolding toxic proteins fold to their native and nontoxic formation, as our common conception. In this review, we analyze the recent perceptions and findings of molecular chaperones biology in the two degradation pathways and their pathological attribution in several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and others. It is worthy noticing that some of the HSPs can not only block the protein aggregation in the early stages, but also have promising effect on attenuating the formation of fibrils. Further more, when the degradation pathways are too weak to degrade all the toxic soluble proteins, molecular chaperones can also help to sequenstrate the toxic proteins into inclusion bodies. However, whether it is good or bad is still unclear. Therefore, the study of HSPs might shed new light on not only the mechanisms of protein synthesis and degradation, but also the possible therapeutic targets of fibril formation associating diseases.
蛋白质合成与降解的动态平衡对细胞存活至关重要。大多数与年龄相关的神经退行性疾病的特征是异常蛋白聚集体在受影响的大脑区域积累。细胞内蛋白质代谢的主要途径是泛素蛋白酶体系统 (UPS) 和自噬溶酶体途径 (ALP)。它们协同降解浪费的蛋白质，并相互作用以应对病理状况，其中分子伴侣通过协助蛋白质靶向蛋白酶体或自噬来发挥集体作用。已知在许多组织和器官中，随着年龄的增长，细胞内蛋白质降解功能下降。不能发挥其功能可能是细胞无法适应应激条件的基础，导致错误折叠蛋白沉积和包涵体形成的加速过程，并最终导致神经退行性变。分子伴侣的功能之一是帮助新合成的或错误折叠的有毒蛋白质折叠成其天然的无毒形式，这是我们的共识。在这篇综述中，我们分析了分子伴侣生物学在这两种降解途径中的最新认识和发现，以及它们在几种神经退行性疾病中的病理归因，如帕金森病 (PD)、阿尔茨海默病 (AD)、亨廷顿病 (HD) 等。值得注意的是，一些 HSPs 不仅可以在早期阻止蛋白质聚集，而且对减轻纤维形成也有很好的效果。此外，当降解途径太弱而无法降解所有有毒可溶性蛋白质时，分子伴侣还可以帮助将有毒蛋白质序列化为包涵体。然而，这是好是坏仍不清楚。因此，HSPs 的研究不仅可能揭示蛋白质合成和降解的机制，还可能为与纤维形成相关的疾病提供潜在的治疗靶点。
