E-Thesis 85 views 16 downloads
Interplay between cholesterol homeostasis and neural development in vitro / EMILY STONELAKE
Swansea University Author: EMILY STONELAKE
DOI (Published version): 10.23889/SUThesis.72012
Abstract
Cholesterol metabolism plays a critical role in brain development, with dysregulated cholesterol homeostasis implicated in the pathogenesis of multiple neural developmental disorders. However, regulation of cholesterol homeostasis and it impact on human neural development remains to be fully underst...
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Swansea
2026
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Wang, Y., and Li, M. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa72012 |
| Abstract: |
Cholesterol metabolism plays a critical role in brain development, with dysregulated cholesterol homeostasis implicated in the pathogenesis of multiple neural developmental disorders. However, regulation of cholesterol homeostasis and it impact on human neural development remains to be fully understood. Both cholesterol itself as well as specific oxidised metabolites of cholesterol, known as oxysterols, are demonstrated to act as bioactive signalling molecules and interact with key signalling pathways involved in neural developmental processes. However, there is a lack of evidence for the presence of these molecules endogenously in developing human neural cells and it remains to be determined which of these sterols may be responsible for aberrant human neurogenesis. In this thesis, temporal sterolomic profiles were generated from in vitro models of human pluripotent stem cell (hPSC)-derived cortical neurons and astrocytes to investigate cholesterol homeostasis and identify the presence of bioactive sterols involved in key neurodevelopmental signalling pathways. We confirmed the endogenous presence of several oxysterols in human neuronal cultures, including 24S-hydroxycholesterol (24S-HC) and 24S,25-epoxycholesterol (24S,25-EC), both implicated in neurogenesis. Notably, 24S-HC was identified as the predominant oxysterol, consistent with its abundance in the adult human brain. hPSC-derived astrocytes were similarly shown to produce both 24S-HC and 24S,25-EC and express the enzyme CYP46A1, indicating active sterol metabolism. This sterolomic profiling was further applied to a model of neural developmental disorder associated with the 15q11.2 copy number variation (CNV), which demonstrated both aberrant neurogenesis and significant alterations in cholesterol metabolism and biosynthesis. Collectively, these findings establish an in vitro framework for investigating the role of cholesterol dysregulation in neurodevelopmental disorders and provide new insight into the sterolomic profiles of developing human neural cells. |
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| Keywords: |
Oxysterol, Cholesterol metabolism, Neurogenesis, Human Pluripotent Stem Cells (hPSCs), CYFIP1 |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
BBSRC SWBio Doctoral Training Partnership |