Item Details

title

STUDIES ON DYSREGULATION OF DE NOVO PROTEIN SYNTHESIS IN DOWN SYNDROME AND ALZHEIMER’S DISEASE

author

Wang, Xin

abstract

Neurodegenerative diseases are becoming increasingly prevalent worldwide as the population aging is accelerating, having a significant socioeconomic impact on society. However, the underlying mechanisms of neurodegenerative diseases are still not well understood. Due to limited understanding of these diseases, by now there are no satisfying treatments available. Thus, it’s imperative to further elucidate the underlying mechanisms and develop corresponding therapies for these diseases. Synaptic dysfunction is a major characteristic and underlying cause of neurodegenerative diseases. Normal synaptic function requires proteostasis. As one of the core processes in proteostasis, dysregulation of de novo protein synthesis (mRNA translation) has been highlighted in many neurodegenerative diseases. Down syndrome (DS) and Alzheimer’s disease (AD) are closely related neurological diseases, with almost all individuals with DS developing AD-like pathologies after age of 40. The extent and nature of de novo protein synthesis dysregulation in these two neurological diseases are not fully understood. In Chapter I, I explored whether eEF2K signaling, a master regulator of elongation phase in protein synthesis, was dysregulated in DS. eEF2K can phosphorylate its substrate eEF2, preventing it from binding to ribosome to facilitate the translocation of tRNA from A site to P site in ribosome and leading to inhibition of de novo protein synthesis. In the brains of DS patients and two DS mouse models, eEF2 phosphorylation was significantly increased, thereby inhibiting de novo protein synthesis. Suppression of eEF2 phosphorylation by eEF2K knockdown could restore de novo protein synthesis, alleviate morphological synaptic defects and electrophysiological synaptic dysfunctions, and improve cognitive deficits in the two mouse models of DS. A proteomic study in Dp16 mouse model suggested that genetic suppression of eEF2K in Dp16 mice could promote protein synthesis-related pathways and synaptogenesis-related proteins. Exploration of upstream regulators of eEF2K signaling found that PQBP1 was downregulated in the hippocampus of both DS patients and Ts65Dn mouse model. Overexpression of PQBP1 in the hippocampus of Ts65Dn mice by AAV injection could reverse eEF2K signaling dysregulation, alleviate synaptic dysfunction and improve cognitive deficits. Furthermore, treatment with small-molecule eEF2K inhibitors in Ts65Dn mice could effectively suppress eEF2K activity, restore de novo protein synthesis, ameliorate synaptic dysfunction and improve cognitive deficits, paving the way for future translational study in DS patients. In summary, eEF2K signaling was dysregulated in the brains of both DS patients and mouse models, and either genetic or pharmacological suppression of this signaling could restore proteostasis, alleviate synaptic dysfunction and improve cognitive deficits in DS mouse models, suggesting eEF2K signaling could be a therapeutic target for the cognitive impairments of DS. In Chapter II, I combined bioorthogonal noncanonical amino acid tagging, which specifically labels newly synthesized proteins, and proteomics to explore dysregulation of de novo proteome in a mouse model of AD. In-depth bioinformatic analysis revealed that proteins involved in synaptic transmission, synaptic plasticity, dendritic spine morphogenesis and mitochondria metabolism were enriched in the de novo proteome of AD mice. These findings provided insights into future investigations of the molecular signaling mechanisms underlying AD and related dementias. Overall, de novo protein synthesis is dysregulated in DS and AD. Restoration of proteostasis by targeting regulators of protein synthesis, especially elongation phase, might be a feasible therapy for the cognitive impairments in the two neurological diseases.

subject

Alzheimer's disease

de novo protein synthesis

Down syndrome

eukaryotic elongation factor 2 kinase

contributor

Ma, Tao (advisor)

Raab-Graham, Kimberly (committee member)

Ma, Tao (committee member)

Milligan, Carol (committee member)

Lin, Hui-Kuan (committee member)

Orr, Miranda (committee member)

date

2023-07-25T17:48:43Z (accessioned)

2023 (issued)

degree

Neuroscience (discipline)

embargo

2028-05-13 (terms)

2028-05-13 (liftdate)

identifier

http://hdl.handle.net/10339/102268 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation