The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.
The unfolded protein response in neurodegenerative diseases: a neuropathological perspective.
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DOI：
10.1007/s00401-015-1462-8
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发表时间：
2015-09
影响因子：
12.7
通讯作者：
Hoozemans JJ
中科院分区：
文献类型：
--
作者：
Scheper W;Hoozemans JJ
未折叠蛋白反应(UPR)是内质网(ER)对蛋白质折叠障碍的应激反应。所谓的内质网应激传感器PERK、IRE1和ATF6在UPR的启动和调节中起着核心作用。错误折叠和聚集的蛋白质堆积是神经退行性疾病的共同特征。随着UPR的基本机制的发现，人们产生了这样的想法，即UPR或其部分机制可能涉及阿尔茨海默病、帕金森氏病、肌萎缩侧索硬化症和普里恩病等神经退行性疾病。在过去的十年里，越来越多的关于神经退行性变的研究涉及到了UPR。UPR参与了人类不同神经疾病的神经病理学研究，以及神经退行性变的细胞和小鼠模型。使用不同疾病模型的研究显示，UPR在神经退行性变过程中的作用和功能存在差异，这往往可以归因于方法学的不同。在这篇综述中，我们将讨论对人脑材料的研究对于解释UPR在神经疾病中的作用的重要性。我们将讨论神经退行性疾病中UPR激活的证据，并讨论研究UPR激活及其与脑病理的联系的方法。最近，通过抑制UPR的特定介质的功能，UPR被认为是治疗和预防神经退行性变的药物治疗的靶点。一些临床前研究表明，在不同的神经退行性变模型中，这种方法针对UPR机制，特别是PERK途径的概念得到了验证，并产生了自相矛盾的结果。这些观察的承诺将需要进一步的支持，澄清观察到的疾病模型之间的差异，以及从人类神经病理学获得更多的洞察力。
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology.