Journal Article

Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome

Keene, C. Dirk, Yang, Qian, Ryazanov, Alexey G., Ma, Tao, Wang, Xin, Zhou, Xueyan

2024

Overview

INTRODUCTION Cognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. METHODS We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology. RESULTS We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS‐associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long‐term synaptic plasticity failure, and cognitive impairments. DISCUSSION Our data suggested that eEF2K signaling dysregulation mediates DS‐associated synaptic and cognitive impairments. Highlights Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.

• Publisher: John Wiley and Sons Inc
• Subject: Animals / Brain - metabolism / cognition / Cognitive Dysfunction - metabolism / Disease Models, Animal / Down syndrome / Down Syndrome - metabolism / Down Syndrome - pathology / Elongation Factor 2 Kinase - genetics / Elongation Factor 2 Kinase - metabolism / eukaryotic elongation factor 2 kinase / Female / Humans / Male / Mice / Mice, Transgenic / mouse model / Peptide Elongation Factor 2 - metabolism / Phosphorylation / protein synthesis / Synapses - metabolism / Synapses - pathology / synaptic plasticity