All ETDs from UAB

Advisory Committee Chair

Rita Cowell

Advisory Committee Members

Sami Barmada

Sara Cooper

Jeremy Day

Sunil Sudarshan

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neuronal energy production is critical to the function of the entire central nervous system. Without enough ATP, neurons are not able to maintain their synaptic structure or activity, leading to a circuit-wide dysregulation, affecting movement and memory. The main process for ATP production in neurons is oxidative phosphorylation, which is supported by several proteins encoded by nuclear DNA. Transcription of nuclear DNA is regulated by DNA-binding transcription factors and co-activators which recruit other members of the transcription initiation complex to induce gene expression. While important basally, during neurodegenerative diseases such as Parkinson’s Disease, the transcription of these genes is altered before the onset of neuron death. Factors that are proposed to be critical to gene expression in neurons include peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and the estrogen-related receptors (ERRα/β/γ). The ERRs bind DNA and engage PGC-1α and the rest of the transcriptional machinery to activate genes related to the electron transport chain, structural support of synapses, and calcium buffering. Here, we not only demonstrate that ERRs are required for PGC-1α-dependent gene expression in neurons, but that ERRγ plays multiple roles in transcriptional regulation including initiation, mRNA editing, and splicing. To do so we used a wide array of -omics assays to examine the network of proteins interacting with ERRγ to influence gene expression in a neuron-like cell. We used RNA-seq with ERRγ or PGC-1α overexpression to reveal responsive genes, proximity biotin-labeling of iv proteins within 10 nm of ERRγ to identify putative interactors, and validation of responsive genes and interactors independent of the biotin labeling. We generated a protein-protein interaction network in a neuron-specific context to provide a ranked list of targetable ERRγ interactors to screen for drug target viability. Altogether, this thesis provides an unbiased framework for future experiments examining ERRγ and its interactors in the context of neuronal health and disease, with the potential to provide strategies for therapeutic manipulation of mitochondrial and synaptic gene regulation in neurodegenerative diseases.

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