Singh Rimaljot, Kaur Navpreet, Choubey Vinay, Dhingra Neelima, Kaur Tanzeer
Department of Biophysics, Panjab University Chandigarh, India.
Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia.
Brain Res. 2024 Mar 1;1826:148742. doi: 10.1016/j.brainres.2023.148742. Epub 2023 Dec 29.
The Endoplasmic reticulum (ER), a critical cellular organelle, maintains cellular homeostasis by regulating calcium levels and orchestrating essential functions such as protein synthesis, folding, and lipid production. A pivotal aspect of ER function is its role in protein quality control. When misfolded proteins accumulate within the ER due to factors like protein folding chaperone dysfunction, toxicity, oxidative stress, or inflammation, it triggers the Unfolded protein response (UPR). The UPR involves the activation of chaperones like calnexin, calreticulin, glucose-regulating protein 78 (GRP78), and Glucose-regulating protein 94 (GRP94), along with oxidoreductases like protein disulphide isomerases (PDIs). Cells employ the Endoplasmic reticulum-associated degradation (ERAD) mechanism to counteract protein misfolding. ERAD disruption causes the detachment of GRP78 from transmembrane proteins, initiating a cascade involving Inositol-requiring kinase/endoribonuclease 1 (IRE1), Activating transcription factor 6 (ATF6), and Protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathways. The accumulation and deposition of misfolded proteins within the cell are hallmarks of numerous neurodegenerative diseases. These aberrant proteins disrupt normal neuronal signalling and contribute to impaired cellular homeostasis, including oxidative stress and compromised protein degradation pathways. In essence, ER stress is defined as the cellular response to the accumulation of misfolded proteins in the endoplasmic reticulum, encompassing a series of signalling pathways and molecular events that aim to restore cellular homeostasis. This comprehensive review explores ER stress and its profound implications for the pathogenesis and progression of neurodegenerative diseases.
内质网（ER）是一种关键的细胞器，通过调节钙水平并协调蛋白质合成、折叠和脂质生成等重要功能来维持细胞内稳态。内质网功能的一个关键方面是其在蛋白质质量控制中的作用。当由于蛋白质折叠伴侣功能障碍、毒性、氧化应激或炎症等因素导致错误折叠的蛋白质在内质网中积累时，会触发未折叠蛋白反应（UPR）。UPR涉及钙连蛋白、钙网蛋白、葡萄糖调节蛋白78（GRP78）和葡萄糖调节蛋白94（GRP94）等伴侣蛋白的激活，以及蛋白质二硫键异构酶（PDI）等氧化还原酶的激活。细胞采用内质网相关降解（ERAD）机制来对抗蛋白质错误折叠。ERAD破坏会导致GRP78从跨膜蛋白上脱离，引发一个涉及肌醇需求激酶/核糖核酸内切酶1（IRE1）、激活转录因子6（ATF6）和蛋白激酶RNA样内质网激酶（PERK）途径的级联反应。错误折叠蛋白在细胞内的积累和沉积是许多神经退行性疾病的标志。这些异常蛋白会破坏正常的神经元信号传导，并导致细胞内稳态受损，包括氧化应激和蛋白质降解途径受损。本质上，内质网应激被定义为细胞对在内质网中错误折叠蛋白积累的反应，包括一系列旨在恢复细胞内稳态的信号通路和分子事件。这篇综述探讨了内质网应激及其对神经退行性疾病发病机制和进展的深远影响。
