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ISR activation mediates the behavioral and neurophysiological abnormalities in Down syndrome

ABSTRACT: Down syndrome (DS) is the most common genetic cause of intellectual disability and a major biomedical concern. Despite a general consensus that protein homeostasis is essential for normal brain function, little is known about its role in DS. Here, we show that the integrated stress response (ISR)—a conserved signaling network that maintains proteostasis by controlling protein synthesis—is activated in the brains of DS mice and individuals with DS, leading to reduced translation. Genetic and pharmacological suppression of the ISR, either by inhibiting the ISR-initiating double-stranded RNA-activated protein kinase (PKR) or boosting the function of the eIF2•eIF2B complex, which becomes limiting upon ISR activation, de-repressed translation, reversed enhanced inhibitory synaptic transmission, and rescued the deficits in synaptic plasticity and memory in DS mice. Our findings unveil a crucial role for the ISR in DS pathophysiology and suggest tuning of the ISR as a promising therapeutic intervention for DS.

ORGANISM(S): Mus musculus

PROVIDER: GSE138371 | GEO | 2019/11/02

REPOSITORIES: GEO

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Project description:Purpose: The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We performed RNA-seq analysis of cerebellum collected from mice harboring a homozygous point mutation in eIF2B5 (HO R191H), a mutation that causes a severe form of VWM in humans and compared gene expression to wildtype age-matched littermates to identify transcriptomic differences at early, mid and late time points during disease progression. We also performed RNA-seq on cerebellum collected from animals treated with the eIF2B activator 2BAct for 1 month to determine to what extent small molecule treatment could normalize the VWM transcriptome. Methods: Samples were collected at 2, 5, and 7 months of age. In addition, HO R191H and WT mice treated with and without with the eIF2B activator 2BAct for 1 month were profiled. RNA-seq libraries were prepared using purified RNA isolated from frozen tissue using the RNeasy Mini kit. RNA quality and concentration were assayed using a Fragment Analyzer instrument. RNA-seq libraries were prepared using the TruSeq Stranded Total RNA kit paired with the Ribo-Zero rRNA removal kit. Libraries were sequenced on an Illumina HiSeq 4000 instrument. For the experiment comparing different ages, N = 3 males/genotype/time point. For the 4-week 2BAct treatment experiment, N = 3 females/condition. Conclusions: HO R191H mutant brains show an elevated gene expression signature of the Integrated Stress Reponse in mice as early as 2 months, preceding the appearance of overt pathology in these animals. The expression of the ISR-related genes does not significantly increases at 5 months and 7 months of age. One month of treatment with 2BAct completely prevented the expression of ISR-related in genes in 2 month old animals.

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ISR activation mediates the behavioral and neurophysiological abnormalities in Down syndrome

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