未折叠蛋白反应
蛋白质稳态
神经退行性变
内质网
神经科学
医学
蛋白质折叠
背景(考古学)
细胞生物学
生物
蛋白质聚集
疾病
病理
古生物学
作者
Claudio Hetz,Smita Saxena
标识
DOI:10.1038/nrneurol.2017.99
摘要
The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network - particularly disturbances to the function of endoplasmic reticulum (ER) - are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.
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