Research Article

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

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Science  15 Nov 2019:
Vol. 366, Issue 6467, pp. 843-849
DOI: 10.1126/science.aaw5185

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Tuning stress protects cognition

Down syndrome (DS) is a chromosomal disorder that occurs when a person has an extra copy of chromosome 21. DS causes intellectual disabilities, among other health issues, but little is known about the mechanisms underlying the memory deficits in DS. Zhu et al. used a multidisciplinary approach to show that a defect in integrated stress response, a conserved pathway that controls protein homeostasis, can explain the cognitive and neuronal deficits in a mouse model of DS (see the Perspective by Halliday and Mallucci). These insights into the biological basis underlying DS could potentially help in the design of treatments for this condition.

Science, this issue p. 843; see also p. 797


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.

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