Objective:

To investigate whether suppression of eEF2 phosphorylation can alleviate synaptic failure and cognitive deficits in mouse models of Down Syndrome. 

Background:

Down syndrome (DS) is the most common cause of intellectual disability. Cognitive impairment including dementia is a core feature of DS and the leading cause of dependence in people with DS. Currently there is no effective treatment for the cognitive deficits of DS, and the neurobiological mechanisms underlying DS-associated cognitive impairment remain unclear, hampering development of novel therapeutics. Maintenance of long-term synaptic plasticity and memory requires integral protein synthesis (mRNA translation) capacity. Recent studies indicate a role of translation dysregulation in multiple neurological disorders characterized by cognitive impairments including DS. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in disruption of peptide growth and thus inhibition of de novo protein synthesis. 

Design/Methods:

We checked levels of eEF2 phosphorylation in the brains of DS patients and controls as well as in two mouse models of DS. We then knocked down eEF2K in the two mouse models and systematically evaluated whether suppression of eEF2 phosphorylation could alleviate synaptic failure and cognitive deficits in the two mouse models. Lastly, we used a small-molecule eEF2K inhibitor to treat DS mice and evaluated its efficacy. 

Results:

eEF2K signaling was dysregulated in the brain of DS patients and two DS mouse models. Inhibition of eEF2 phosphorylation through knockdown of eEF2K in two different 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. Treatment with small-molecule eEF2K inhibitors ameliorated synaptic dysfunction and improved cognitive deficits in DS mice. 

Conclusions:

eEF2K signaling dysregulation could play a critical role in mediating DS-associated synaptic and cognitive impairments, and targeting eEF2K signaling could be an effective therapeutic strategy for DS.