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Interplay between cholesterol homeostasis and neural development in vitro / EMILY STONELAKE

Swansea University Author: EMILY STONELAKE

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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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Published: Swansea 2026
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Wang, Y., and Li, M.
URI: https://cronfa.swan.ac.uk/Record/cronfa72012
first_indexed 2026-06-04T11:19:14Z
last_indexed 2026-06-05T10:54:55Z
id cronfa72012
recordtype RisThesis
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spelling 2026-06-04T12:23:36.4914474 v2 72012 2026-06-04 Interplay between cholesterol homeostasis and neural development in vitro ac63fa1b1043ca2339d4f0a2e20e7d48 EMILY STONELAKE EMILY STONELAKE true false 2026-06-04 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. E-Thesis Swansea Oxysterol, Cholesterol metabolism, Neurogenesis, Human Pluripotent Stem Cells (hPSCs), CYFIP1 19 5 2026 2026-05-19 10.23889/SUThesis.72012 COLLEGE NANME COLLEGE CODE Swansea University Wang, Y., and Li, M. Doctoral Ph.D BBSRC SWBio Doctoral Training Partnership BBSRC SWBio Doctoral Training Partnership 2026-06-04T12:23:36.4914474 2026-06-04T12:08:57.4814040 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science EMILY STONELAKE 1 72012__36862__41aaafa9358f4d3e921ece945e0ff703.pdf 2026_Stonelake_E.final.72012.pdf 2026-06-04T12:16:59.3155855 Output 5877873 application/pdf E-Thesis – open access true Copyright: the author, Emily Jane Stonelake, 2026. true eng
title Interplay between cholesterol homeostasis and neural development in vitro
spellingShingle Interplay between cholesterol homeostasis and neural development in vitro
EMILY STONELAKE
title_short Interplay between cholesterol homeostasis and neural development in vitro
title_full Interplay between cholesterol homeostasis and neural development in vitro
title_fullStr Interplay between cholesterol homeostasis and neural development in vitro
title_full_unstemmed Interplay between cholesterol homeostasis and neural development in vitro
title_sort Interplay between cholesterol homeostasis and neural development in vitro
author_id_str_mv ac63fa1b1043ca2339d4f0a2e20e7d48
author_id_fullname_str_mv ac63fa1b1043ca2339d4f0a2e20e7d48_***_EMILY STONELAKE
author EMILY STONELAKE
author2 EMILY STONELAKE
format E-Thesis
publishDate 2026
institution Swansea University
doi_str_mv 10.23889/SUThesis.72012
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description 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.
published_date 2026-05-19T06:39:50Z
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score 11.108446

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