Remondelli Paolo, Renna Maurizio
Dipartimento di Medicina, Chirurgia e Odontoiatria "Scuola Medica Salernitana", Università degli Studi di SalernoSalerno, Italy.
Cambridge Institute for Medical Research, Department of Medical Genetics, Wellcome Trust, Addenbrooke's Hospital, University of CambridgeCambridge, United Kingdom.
Front Mol Neurosci. 2017 Jun 16;10:187. doi: 10.3389/fnmol.2017.00187. eCollection 2017.
In eukaryotic cells, the endoplasmic reticulum (ER) is the cell compartment involved in secretory protein translocation and quality control of secretory protein folding. Different conditions can alter ER function, resulting in the accumulation of unfolded or misfolded proteins within the ER lumen. Such a condition, known as ER stress, elicits an integrated adaptive response known as the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway. Conversely, in prolonged cell stress or insufficient adaptive response, UPR signaling causes cell death. ER dysfunctions are involved and contribute to neuronal degeneration in several human diseases, including Alzheimer, Parkinson and Huntington disease and amyotrophic lateral sclerosis. The correlations between ER stress and its signal transduction pathway known as the UPR with neuropathological changes are well established. In addition, much evidence suggests that genetic or pharmacological modulation of UPR could represent an effective strategy for minimizing the progressive neuronal loss in neurodegenerative diseases. Here, we review recent results describing the main cellular mechanisms linking ER stress and UPR to neurodegeneration. Furthermore, we provide an up-to-date panoramic view of the currently pursued strategies for ameliorating the toxic effects of protein unfolding in disease by targeting the ER UPR pathway.
在真核细胞中，内质网（ER）是参与分泌蛋白转运和分泌蛋白折叠质量控制的细胞区室。不同的条件可改变内质网功能，导致内质网腔中未折叠或错误折叠蛋白的积累。这种情况称为内质网应激，引发一种称为未折叠蛋白反应（UPR）的综合适应性反应，其目的是恢复分泌途径内的蛋白质稳态。相反，在长期的细胞应激或适应性反应不足的情况下，UPR信号传导会导致细胞死亡。内质网功能障碍参与并促成了包括阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症在内的几种人类疾病中的神经元变性。内质网应激及其称为UPR的信号转导途径与神经病理变化之间的相关性已得到充分证实。此外，许多证据表明，对UPR进行基因或药物调节可能是将神经退行性疾病中进行性神经元损失降至最低的有效策略。在这里，我们综述了描述内质网应激和UPR与神经退行性变之间主要细胞机制的最新研究结果。此外，我们提供了一个最新的全景图，展示了目前通过靶向内质网UPR途径来改善疾病中蛋白质错误折叠毒性作用所采用的策略。
