Format

Send to

Choose Destination
Science. 2019 Nov 15;366(6467):843-849. doi: 10.1126/science.aaw5185.

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

Author information

1
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
2
Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA.
3
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
4
Division of Biostatistics, Dan L Duncan Comprehensive Cancer Center, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
5
Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
7
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
8
Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA. costamat@bcm.edu peter@walterlab.ucsf.edu.
9
Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
10
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. costamat@bcm.edu peter@walterlab.ucsf.edu.

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.

PMID:
31727829
DOI:
10.1126/science.aaw5185

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center