Santos, Chloe; (2022) Investigating the Cause of Central Nervous System Defects in Glycine Decarboxylase-Deficient Mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glycine decarboxylase (GLDC) is part of the glycine cleavage system, which is a highly conserved multi-enzyme complex specific to mitochondrial folate one carbon metabolism. Mutations in GLDC are associated with common birth defects: neural tube defects (NTDs) and congenital hydrocephalus, and are known to cause Non-Ketotic Hyperglycinaemia (NKH) - a rare neurometabolic disease in humans. Neural tube defects (NTDs) are the second most common global congenital abnormality, which arise when the neural tube - the precursor to the brain and spinal cord - fails to close. We generated and characterised Gldc-deficient (GldcGT1/GT2) gene trap mice as a model to investigate the causative mechanisms of NTDs. In this study, I delve into transcriptomic and metabolomic changes caused by GLDC loss of function. Our data highlight disruptions in mitochondrial abundance and redox balance, which imply that mitochondrial dysfunction and oxidative stress in the neuroepithelium may contribute to the causation of NTDs in Gldc-deficient embryos. In addition, a proportion of Gldc-deficient mice develop hydrocephalus, which manifests as enlarged brain ventricles (ventriculomegaly) at late foetal stages. It is not known whether excess glycine or 1C deficiency leads to hydrocephalus. Here, my findings show that the lack of glycine-derived 1C units may lead to the abnormal development of the subcommissural organ, which is likely to underlie aqueduct stenosis that results in a non-communicating hydrocephalus. Furthermore, to investigate tissue and cell-specific requirements for GLDC during development, I characterise the Gldc mRNA and protein expression patterns in mouse and human tissues. We also use genetic approaches to generate conditional knockout and rescue models to assess the tissue-specific requirements for Gldc in neural tube closure and foetal brain development. Understanding the causative factors of these congenital phenotypes will advance our approaches towards preventative measures and treatments.

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