# Targeting protein synthesis dysregulation in Down syndrome-associated cognitive impairment with aging

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $1,142,664

## Abstract

Project Summary/Abstract
Down syndrome (DS) is one of the most common forms of intellectual disability associated with trisomic repeat
of chromosome 21. Impaired cognition including dementia is a hallmark of DS, but the underlying
cellular/molecular mechanisms remain unclear, hampering our ability to develop effective therapy for cognitive
defects in people with DS. People with DS are at much higher risk for developing Alzheimer’s disease (AD), a
devastating neurodegenerative disease and the most common of dementia in elderly. Starting at middle age,
majority of DS patients develop neuropathology and dementia syndromes resembling AD. Long-term memory
and synaptic plasticity require de novo protein synthesis, and recent studies indicate that mRNA translation
impairments contribute to cognitive syndromes in several neuronal diseases including AD, independent of brain
Amyloid beta pathology. Driven by previous studies and our preliminary data, the goal of this project is to
determine whether upregulation of the capacity for de novo protein synthesis, via suppression of eEF2K
and eEF2 phosphorylation, will improve multiple aging-related pathophysiology in DS including synaptic
failure and cognitive deficits. Three specific aims have been designed to test this hypothesis. Aim 1 seeks to
determine whether inhibition of eEF2K and eEF2 phosphorylation alleviates synaptic plasticity impairments in
mouse models of Down syndrome. Aim 2 is to determine whether suppression of eEF2K and eEF2
phosphorylation can improve DS-associated cognitive deficits. Aim 3 is to elucidate mechanisms underlying DS
pathophysiology associated with dysregulation of eEF2K/eEF2 signaling cascade. The project proposes in-depth
analyses using multiple approaches in neuroscience, including synaptic electrophysiology, pharmacology,
imaging, mouse genetics, and behavioral tests. We will employ novel genetic models and assays to assess de
novo protein synthesis in neurons including bioorthogonal noncanonical amino acid tagging (BONCAT) with a
proximity ligation assay (PLA) (BONCAT-PLA). Combined with mass spectrometry/proteomics approach, we
expect to reveal identities of proteins in DS brains whose synthesis is dysregulated because of abnormal
eEF2K/eEF2 signaling. Findings from this project will contribute to our understanding of the cellular/molecular
signaling mechanisms underlying DS-associated cognitive impairments. Results from this project could inform
eventual development of novel therapeutic strategies for DS-related cognitive syndromes, for which no effective
treatments exist.

## Key facts

- **NIH application ID:** 10295206
- **Project number:** 1R01AG073823-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Tao Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,142,664
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295206

## Citation

> US National Institutes of Health, RePORTER application 10295206, Targeting protein synthesis dysregulation in Down syndrome-associated cognitive impairment with aging (1R01AG073823-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10295206. Licensed CC0.

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