MRC Toxicology Unit, Leicester, UK.
Department of Clinical Neurosciences, University of Cambridge, UK.
FEBS J. 2019 Jan;286(2):342-355. doi: 10.1111/febs.14422. Epub 2018 Mar 11.
The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases.
未折叠蛋白反应（UPR）是一种高度保守的蛋白质质量控制机制，对内质网（ER）应激做出反应。信号通过 PERK、IRE1 和 ATF6 这三个分支进行传递，它们共同提供协调的反应，有助于克服破坏的蛋白质稳定性。PERK 分支的激活主要导致全局翻译速率的迅速降低，而 IRE1 和 ATF6 分支的信号诱导转录反应，导致伴侣蛋白和蛋白质降解机制的组成部分的表达。蛋白质错误折叠的神经退行性疾病表现出蛋白质稳定性的破坏，作为生化特征。在疾病动物模型的大脑中，以及在许多此类疾病的人类死后组织中，可观察到 UPR 诱导的标志物，特别是 PERK 途径与疾病进展密切相关。最近的研究表明，UPR 信号的失调是神经退行性变的主要致病机制，PERK 途径的遗传和药理学调节可导致有效的神经保护作用。针对异常的 UPR 信号是新治疗策略的重点，这对神经退行性疾病的广泛范围可能是有益的。
