Exploring the molecular mechanisms of Rett syndrome
Citation:
SANFELIU BOSCH, ALBERT, Exploring the molecular mechanisms of Rett syndrome, Trinity College Dublin.School of Medicine, 2020Download Item:
Abstract:
Rett Syndrome (RTT) is a severe neurological disorder that onsets between 6 to 18 months of age, after a period of apparently normal development. RTT affects approximately 1 in every 10000 to 15000 live births and is characterised by an array of symptoms that can include severe intellectual disability, motor impairment, stereotypical hand movements, autistic features, seizures and cardiorespiratory complications. The most common cause of RTT are mutations in the X-linked gene MECP2, which encodes for Methyl-CpG-Binding Protein 2 (MeCP2). The main function of MeCP2 is the epigenetic transcriptional control of large number of genes, which turns RTT into a very complex condition. While efforts have been made to understand the physiopathology of RTT, most of its underlying mechanisms are still unknown. For this reason, the main goal of this work is to provide evidence that can help understand what processes take place between the mutations in MECP2 and the subsequent clinical manifestation. This goal was addressed using three different approaches, which are reflected in the three chapters of this thesis.
The aim of the first chapter is to discover molecular mechanisms that are dysregulated both in the blood and the brain of RTT, which could give a broader understanding of the disease and provide clues for biomarker discovery. In order to do this, RNA sequencing was used to analyse changes in gene expression in the brain and blood of a murine model of RTT ¬ Mecp2-null mice¬. This first chapter revealed the potential involvement in RTT of the genes Ube2v1 and Serpina1c, as well as a potential involvement of mechanisms related to haemostasis and nitric oxide metabolism.
The second chapter tackles the variability across the multiple studies performed on mouse models of RTT. It is aimed to identify genes consistently reported by these studies, and thus more likely to be involved in the biology of RTT. By merging the results of 36 different experiments, a list of 404 genes commonly dysregulated in RTT models was generated. A functional analysis of these genes revealed a plethora of implicated pathways and biological functions, including oxytocin, MAPK, PI3K, Calcium and cAMP signalling, axon guidance, circadian entrainment, several synaptic pathways, inflammation and stress.
Finally, the third chapter looks at RTT from a therapeutic perspective, by focusing on the mechanisms modulated by the treatment of RTT with Insulin-Like Growth Factor 1 (IGF-1). IGF-1 has been shown to effectively ameliorate the symptoms Mecp2-null mice, but its exact mechanism of action is unknown. For this reason, the aim of this chapter was to shed light on the biological processes, both in the brain and peripherally, influenced by IGF-1 treatment of Mecp2-null mice. Mecp2-null mice and wild-type controls were treated with IGF-1 for 5 weeks, after which gene expression levels in their brain and blood were assessed by means of 3 Digital Gene Expression Sequencing. This approach revealed potential pathways of IGF-1 effect in RTT, including inflammation, mitochondrial function, oxidative stress and autophagy.
Sponsor
Grant Number
Wellcome Trust
Science Foundation Ireland (SFI)
Rett Syndrome Foundation
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:ASANFELIDescription:
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Author: SANFELIU BOSCH, ALBERT
Advisor:
Tropea, DanielaPublisher:
Trinity College Dublin. School of Medicine. Discipline of PsychiatryType of material:
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