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Highlights− The first atlas of human 3'QTLs: ~0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals − 3'QTLs could alter polyA motifs and RNA-binding protein binding sites − 3'QTLs can be used to interpret ~16.1% of trait-associated variants − Many disease-associated 3'QTLs contribute to phenotype independent of gene expression .
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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