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.

神经退行性疾病的临床表现是由不同神经元群体功能的选择性改变引起的。许多神经退行性疾病的病理学包括错折叠的蛋白质在大脑中的积累。在生理条件下，蛋白质稳定网络可维持正常的蛋白质折叠，运输和降解。该网络的变化，特别是对内质网（ER）功能的干扰，被认为是导致异常蛋白质聚集的原因。内质网应激会触发信号反应，称为未折叠蛋白反应（UPR），它会诱导适应性程序，从而改善蛋白折叠并促进质量控制机制和降解途径，或者在损伤不可逆转时激活细胞凋亡。在这篇评论中，我们讨论了在定义ER应激对脑疾病的功能性贡献方面的最新进展，包括将UPR与突触功能相关的新证据，这对认知和记忆具有影响。出现一个复杂的概念，其中ER应激的后果可能会根据疾病情况和改变的UPR信号传导途径而大不相同。正在开发使用小分子和基因疗法靶向UPR特定成分的策略，并有望为将来的干预措施延缓或停止神经变性提供有趣的途径。出现一个复杂的概念，其中ER应激的后果可能会根据疾病情况和改变的UPR信号传导途径而大不相同。正在开发使用小分子和基因疗法靶向UPR特定成分的策略，并有望为将来的干预措施延缓或停止神经变性提供有趣的途径。出现一个复杂的概念，其中ER应激的后果可能会根据疾病情况和改变的UPR信号传导途径而大不相同。正在开发使用小分子和基因疗法靶向UPR特定成分的策略，并有望为将来的干预措施延缓或停止神经变性提供有趣的途径。