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

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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.