College of Pharmacy, Al Ain University, Abu Dhabi 112612, UAE.
Core Technology Platforms, New York University Abu Dhabi, Abu Dhabi 129188, UAE.
Int J Mol Sci. 2020 Aug 25;21(17):6127. doi: 10.3390/ijms21176127.
The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.
内质网（ER）是参与蛋白质质量控制和细胞内稳态的重要细胞器。未折叠蛋白的积累会导致内质网应激，随后通过激活未折叠蛋白反应（UPR）、蛋白激酶 R 样内质网激酶（PERK）、肌醇需求转位酶/内切核酸酶 1α（IRE1α）和激活转录因子 6（ATF6）途径来进行适应性反应。然而，细胞应激的持续激活会激活细胞凋亡信号，导致细胞死亡。神经元细胞对蛋白质错误折叠特别敏感，因此内质网和 UPR 功能障碍与许多神经退行性疾病有关，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和朊病毒病等，这些疾病的特征是错误折叠的蛋白质的积累和聚集。在受影响的组织中调节 UPR 的药理学可能有助于治疗和预防神经退行性变。内质网应激、UPR 和神经病理学之间的关联已得到充分证实。在这篇综述中，我们提供了 UPR 在神经退行性疾病中激活的最新证据，随后是针对 UPR 的治疗策略，以及减轻蛋白质错误折叠和聚集的毒性作用。
