Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States.
Int Rev Cell Mol Biol. 2020;350:285-325. doi: 10.1016/bs.ircmb.2019.11.001. Epub 2020 Feb 20.
Neurological diseases are multifactorial, devastating diseases that are causative for various neurodegenerative disorders. Emerging evidence points that accumulation of unfolded, misfolded, insoluble, and damaged proteins inside the CNS cells such as microglia, astrocytes, neurons, oligodendrocytes, pericytes, and endothelial cells, leads to endoplasmic reticulum (ER) stress and dysregulated autophagy, which, in turn, sets the stage for ensuing neuropathogenesis. Studies have also demonstrated that chronic ER stress/unfolded protein response (UPR) activates autophagy, and conversely, that blockade of autophagy aggravates ER stress with ensuing cell death, in turn, leading to the development and progression of neurodegeneration. ER stress and autophagy signaling pathways are thus of particular interest as target(s) for pharmacological intervention for the development of therapeutic strategies for various neurological diseases. Herein, we summarized the current knowledge of chronic ER stress/UPR and autophagy signaling pathways and their regulation in CNS cells such as microglia, astrocytes, neurons, oligodendrocytes, pericytes, and endothelial cells. We also reviewed various neurological diseases wherein ER stress/UPR, and autophagy play key roles and also discussed possible pharmacological interventions involving these processes.
神经疾病是多因素的、破坏性的疾病，是各种神经退行性疾病的病因。新出现的证据表明，未折叠、错误折叠、不溶性和受损蛋白质在中枢神经系统细胞（如小胶质细胞、星形胶质细胞、神经元、少突胶质细胞、周细胞和内皮细胞）内的积累会导致内质网（ER）应激和失调的自噬，进而为随后的神经发病机制奠定基础。研究还表明，慢性 ER 应激/未折叠蛋白反应 (UPR) 会激活自噬，反之，自噬的阻断会加剧 ER 应激和随后的细胞死亡，进而导致神经退行性变的发展和进展。因此，ER 应激和自噬信号通路是药理学干预的特别感兴趣的靶点，可用于开发各种神经疾病的治疗策略。在此，我们总结了慢性 ER 应激/UPR 和自噬信号通路及其在中枢神经系统细胞（如小胶质细胞、星形胶质细胞、神经元、少突胶质细胞、周细胞和内皮细胞）中的调节的最新知识。我们还回顾了 ER 应激/UPR 和自噬在其中发挥关键作用的各种神经疾病，并讨论了涉及这些过程的可能的药理学干预。
