美国贝勒医学院Mauro Costa-Mattioli和美国加州大学旧金山分校Peter Walter研究组合作发现，整合应激反应（ISR）的激活介导了唐氏综合症（DS）的行为和神经生理异常。相关论文发表在2019年11月15日出版的《科学》上。

他们发现，ISR是一种维持蛋白稳定的信号网络，已在DS小鼠和患有DS的个体的大脑中被激活，从而对翻译进行了重新编程。通过抑制ISR诱导的双链RNA激活的蛋白激酶或增强真核翻译起始因子eIF2-eIF2B复合体的功能，来抑制ISR的ISR的遗传和药理作用，并逆转翻译变化和抑制突触传递，来拯救DS小鼠的突触可塑性和长期记忆缺陷。因此，ISR在DS中起着至关重要的作用，这表明对ISR的调整可能会提供有希望的治疗干预方法。

据了解，DS是最常见的智力障碍遗传原因。蛋白质稳态对于正常的大脑功能至关重要，但对其在DS病理生理中的作用知之甚少。

附：英文原文

Title: Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome

Author: Ping Jun Zhu, Sanjeev Khatiwada, Ya Cui, Lucas C. Reineke, Sean W. Dooling, Jean J. Kim, Wei Li, Peter Walter, Mauro Costa-Mattioli

Issue&Volume: 2019/11/15

Abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis is essential for normal brain function, but little is known about its role in DS pathophysiology. In this study, we found that the integrated stress response (ISR)—a signaling network that maintains proteostasis—was activated in the brains of DS mice and individuals with DS, reprogramming translation. Genetic and pharmacological suppression of the ISR, by inhibiting the ISR-inducing double-stranded RNA–activated protein kinase or boosting the function of the eukaryotic translation initiation factor eIF2-eIF2B complex, reversed the changes in translation and inhibitory synaptic transmission and rescued the synaptic plasticity and long-term memory deficits in DS mice. Thus, the ISR plays a crucial role in DS, which suggests that tuning of the ISR may provide a promising therapeutic intervention.

DOI: 10.1126/science.aaw5185

Source:https://science.sciencemag.org/content/366/6467/843