Hu, Hao; (2025) Functional analysis of CYP27A1 in the nervous system. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis-Hao-eVersion.pdf - Accepted Version Access restricted to UCL open access staff until 1 July 2028. Download (17MB)

Abstract

CYP27A1(cholesterol hydroxylase) is a key enzyme in cholesterol metabolism, critical for bile acid(BA) synthesis and lipid homeostasis. Dysfunction in CYP27A1 disrupts BA and lipid metabolism, leading to a rare autosomal recessive lipid storage disease Cerebrotendinous Xanthomatosis(CTX), neurologically characterised by cognitive impairment and white matter abnormalities. While a primary BA chenodeoxycholic acid(CDCA) is used clinically to mitigate some CTX symptoms by restoring BA balance, the underlying mechanisms remain unclear. Herein, I used Cyp27a1 germline knockout mice to investigate the enzyme's functional role in the developing nervous system. Significant defects were observed in interneuron development, including delayed and reduced populations of Parvalbumin-expressing interneurons. Moreover, developmental delays in myelin sheath formation were identified, potentially contributing to broader neurological dysfunction. CYP27A1 deficiency further led to behavioural disorders including anxiety-like behaviours and social interaction deficits. Notably, oral administration of CDCA at specific concentrations rescued neurodevelopmental and behavioural deficits, suggesting the crucial role of BA homeostasis in the brain. Using conditional knockout models via the Cre-loxP recombination system, I demonstrated the impact of Cyp27a1 in neurodevelopment primarily mediated by microglia as early as the neonatal period. RNA sequencing(RNA-seq) in primary microglia evaluated the regulatory role of intracellular BA metabolism in cell cycle progress and lipid metabolism related phagocytosis. Besides, brain metabolomics of E13.5, P0 and P30 identified defected energy metabolism during early development mediated by the BA metabolism disorder. Given the high expression of Cyp27a1 detected in the cingulate cortex, I further investigated potential sensory dysfunction and identified altered responses to both acute chemical and mechanical pain in the absence of Cyp27a1. I also discovered co-expression of Cyp27a1 and Trpm8 in the dorsal root ganglion(DRG) with altered cold sensation, indicating a role for Cyp27a1 in regulating response to cold exposure. Low-input RNA-seq of DRG tissue further identified differentially expressed RNA in the absence of Cyp27a1 highlighting multiple altered synaptic pathways. In conclusion, this study demonstrates the critical role of Cyp27a1 during neurodevelopment and neural functions, uncovering novel functional role of BA metabolism in the nervous system.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item