Neuroscience Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Int J Mol Sci. 2022 Jul 15;23(14):7823. doi: 10.3390/ijms23147823.
In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with stress. Beyond its neuroprotective role, under regimes of chronic or excessive stress, ISR can also promote cell/neuronal death. Given the two-edged sword nature of ISR, many experimental attempts have tried to establish the therapeutic potential of ISR enhancement or inhibition in ALS. This review discusses the complex interplay between ISR and disease progression in different models of ALS, as well as the opportunities and limitations of ISR modulation in the hard quest to find an effective therapy for ALS.
在肌萎缩侧索硬化症（ALS）患者中，皮质和脊髓运动神经元内细胞内稳态的丧失会触发整合应激反应（ISR）的激活，这是一种细胞内信号通路，可重塑翻译并促进旨在应对压力的基因表达程序。除了其神经保护作用外，在慢性或过度应激的情况下，ISR 还可以促进细胞/神经元死亡。鉴于 ISR 的双刃剑性质，许多实验尝试都试图确定 ISR 增强或抑制在 ALS 中的治疗潜力。这篇综述讨论了 ISR 与不同 ALS 模型中疾病进展之间的复杂相互作用，以及在寻找有效的 ALS 治疗方法的艰难探索中，ISR 调节的机会和局限性。
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