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Perez Grovas Saltijeral, Adriana (2025) Investigating the regulation of DNA and RNA modifications in neurocognitive diseases. PhD thesis, University of Nottingham.

PDF (Thesis with corrections) (Thesis - as examined) - Repository staff only until 20 July 2026. Subsequently available to Anyone - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader Available under Licence Creative Commons Attribution. Download (7MB)

Abstract

Dementia is a leading cause of disability in the elderly, with over 55 million people diagnosed worldwide as of 2019. Neurodegenerative dementias result from the progressive and irreversible degeneration of neurons. Epigenetic and epitranscriptomic processes regulate transcriptional and translational activities, mediating gene expression and environmental influences on cell physiology. Such processes are tissue and cell-type specific, change during cellular differentiation and ageing, and are increasingly relevant in understanding disease-modifying mechanisms. Chemical modifications on DNA and RNA, such as methylations, are governed by three families of effector proteins known as writers, readers and erasers. The expression of these DNA and RNA modifications and their effector proteins across brain regions and within cellular environments significantly impacts transcription and translation activities, leading to disease.

This thesis investigated epigenomic and epitranscriptional modifications and their regulatory mechanisms in human brain and the roles they play in neurocognitive diseases. Using RNA sequencing data from brain tissue of individuals with Alzheimer's Disease (AD), Traumatic Brain Injury (TBI), and healthy aged controls, I first examined the expression profiles of 5-methylcytosine DNA (5mC) and RNA (m5C) effector proteins across four brain regions. The expression profiles were further compared between neuropathological Braak and CERAD scores. I found that DNA methylation writers DNMT1, DNMT3A and DNMT3B were increased, while the reader UHRF1 was decreased in AD samples across three brain regions. Changes in abundance were also noted for DNA erasers GADD45B and AICDA across neuropathological load groupings. Additionally, RNA methyltransferases NSUN6 and NSUN7 presented changes in abundance across three brain regions between AD and controls, and along with the reader ALYREF, significant changes were registered between neuropathological groupings. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 and a decrease in NSUN6.

In subsequent chapters, and through fluorescence immunohistochemistry, I assessed the abundance and distribution of novel RNA m3C modification and m5C methyltransferase NSUN5 across neuronal and non-neuronal cell populations and subcellular compartments in human brain tissue from individuals with Mild Cognitive Impairment (MCI), AD, and Lewy Body Diseases (LBD), compared to healthy aged controls. Within the hippocampus, I located m3C RNAs within mitochondria and at postsynaptic sites in healthy aged brain tissue and found increased abundance in neuronal cells compared to non-neuronal cells, particularly in the CA2-3 subregions. I also revealed significantly increased total, mitochondrial-specific, and synaptic-specific m3C across MCI, and LBD compared to controls in all hippocampal regions except the dentate gyrus (DG), where healthy aged tissue had higher synaptic m3C levels than diseased tissue. Similarly, NSUN5’s distribution across the middle frontal gyrus confirmed a cytoplasmic location and uncovered its presence within mitochondria, particularly at mitoribosomes. NSUN5 was more abundant in pyramidal cells compared to interneurons or glial cells, and I observed a decrease in mitochondrial NSUN5 in pyramidal cells of disease tissue across all cortical layers, and an increase in interneurons and glial cells in cortical layer I.

In addition, I performed bisulfite-treated RNA sequencing to investigate m5C RNA modification within human brain. Overall, these findings provide evidence of the regulation of protein pathways disrupted in neurocognitive diseases via multiple pre- and post-transcriptional mechanisms. This study further suggests a novel mitochondrial and synaptic target for RNA m3C modification and identifies RNA methyltransferase NSUN5 as a potential m5C mitoribosomal writer. These insights could pave the way for new therapeutic strategies targeting mitochondrial RNA modifications to treat neurocognitive diseases.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Knight, Helen Miranda Rajkumar, Anto
Keywords:	Alzheimer's disease, dementia, epigenetics, epitranscriptomics, methylation, RNA modifications, DNA modifications
Subjects:	R Medicine > RC Internal medicine
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	80084
Depositing User:	PEREZ GROVAS SALTIJERAL, ADRIANA
Date Deposited:	24 Jul 2025 04:40
Last Modified:	24 Jul 2025 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/80084

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