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The glycine cleavage system in embryonic brain development

Pai, YJ; (2015) The glycine cleavage system in embryonic brain development. Doctoral thesis , UCL (University College London). Green open access

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The glycine cleavage system (GCS) is a multi-enzyme complex localised in the mitochondria and serves as the main catabolic pathway for glycine. It contributes to supply of one-carbon units into folate one-carbon metabolism (FOCM) which utilises them for vital processes such as purines and thymidylate biosynthesis and methylation reactions. This thesis focuses on the role of glycine decarboxylase (Gldc), a member of the GCS, in embryonic development of the brain. It utilises two loss-of-function mouse models for Gldc which were found to exhibit two distinct disease phenotypes: non-ketotic hyperglycinemia (NKH) and neural tube defects (NTDs). The aims of this project are to investigate what effects GCS deficiency has on FOCM, the developmental mechanisms underlying NTDs caused by loss of Gldc expression, and suitability of the Gldc mice models as animal models for classical NKH. NKH is a rare metabolic disease caused by mutations of GCS genes (mainly GLDC) and characterised by accumulation of glycine in body fluids, resulting in severe neurological dysfunction and poor survival. Gldc-deficient mice exhibited features of NKH including elevated glycine, early post-natal lethality, and hydrocephalus. Enlargement of the brain ventricles was found to already be present at late-foetal stage, while glycine levels in whole embryos were already elevated shortly after neurulation. Gldc-deficient embryos also displayed NTDs, a common birth defect of the central nervous system that result from failure of the neural tube to close. Gldc-deficient embryos displayed abnormal folate metabolism, growth retardation and reduced cell proliferation. Supplementation with one-carbon units through dietary means was able to normalise folate profiles, completely rescue the NTDs, and normalise proliferation and growth in Gldc-deficient embryos. Diet-induced folate deficiency and interactions with the Mthfr mutation (which results in a methylation defect) did not exacerbate the NTDs caused by the Gldc mutation. This study provides the first mouse model for classical NKH and suggests that the pathology of NKH begins earlier in development than suspected. It also suggests that Gldc deficiency causes NTDs by reducing the supply of glycine-derived, mitochondrial one-carbon units for FOCM reactions.

Type: Thesis (Doctoral)
Title: The glycine cleavage system in embryonic brain development
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/1471014
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