Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice

Santos, Chloe; Pai, Yun Jin; Mahmood, Maira; Leung, Kit‐Yi; Savery, Dawn; Waddington, Simon; Copp, Andrew J.; Greene, Nicholas D. E.

doi:10.1172/jci132360

Cited by 21 publications

(36 citation statements)

References 36 publications

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“…Pilot experiments were conducted to determine concentrations which did not diminish intake of water (monitored daily) or adversely affect health. Treatment of mice in the control, benzoate or cinnamate treatment groups (Figures 3 and 4) was started from 5 weeks of age in mice that were exposed pre‐natally to maternal administration of sodium formate (30 mg/mL) for the first 15 days of pregnancy in order to prevent structural malformations (neural tube defects or ventriculomegaly) 15,36 …”

Section: Methodsmentioning

confidence: 99%

Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non‐ketotic hyperglycinemia

Leung

Castro

Santos

et al. 2020

J of Inher Metab Disea

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Glycine abundance is modulated in a tissue-specific manner by use in biosynthetic reactions, catabolism by the glycine cleavage system (GCS), and excretion via glycine conjugation. Dysregulation of glycine metabolism is associated with multiple disorders including epilepsy, developmental delay, and birth defects. Mutation of the GCS component glycine decarboxylase (GLDC) in non-ketotic hyperglycinemia (NKH) causes accumulation of glycine in body fluids, but there is a gap in our knowledge regarding the effects on glycine metabolism in tissues. Here, we analysed mice carrying mutations in Gldc that result in severe or mild elevations of plasma glycine and model NKH. Liver of Gldc-deficient mice accumulated glycine and numerous glycine derivatives, including multiple acylglycines, indicating increased flux through reactions mediated by enzymes including glycine-N-acyltransferase and arginine: glycine amidinotransferase. Levels of dysregulated metabolites increased with age and were normalised by liver-specific rescue of Gldc expression. Brain tissue exhibited increased abundance of glycine, as well as derivatives including guanidinoacetate, which may itself be epileptogenic. Elevation of brain tissue glycine occurred even in the presence of only mildly elevated plasma glycine in mice carrying a missense allele of Gldc. Treatment with benzoate enhanced hepatic glycine conjugation thereby lowering plasma and tissue glycine. Moreover, administration of a glycine conjugation pathway intermediate, cinnamate, similarly achieved normalisation of liver glycine derivatives and circulating glycine. Although exogenous benzoate and cinnamate impact glycine levels via activity of glycine-N-acyltransferase, that is not expressed in

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Section: Methodsmentioning

confidence: 99%

Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non‐ketotic hyperglycinemia

Leung

Castro

Santos

et al. 2020

J of Inher Metab Disea

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“…Mitochondrial serine hydroxymethyltransferase 2 (SHMT2) transfers the β-carbon of serine to THF, generating 5,10-methylene-THF that can also be produced from glycine by the activity of glycine decarboxylase (GLDC), an abundant enzyme in astrocytes ( Figure 4.4 ; Li et al, 2018 ). GLDC deficiency induces neural tube defects and hydrocephaly ( Pai et al, 2015 ; Leung et al, 2017 ; Santos et al, 2020 ). The bifunctional enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) or MTHFD2-like (MTHFD2L) then catalyzes the sequential production of 5,10-methenyl-THF and 10-formyl-THF.…”

Section: Mitochondrial Metabolism In Astrocytes and Redox Balancementioning

confidence: 99%

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

et al. 2020

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In the brain, mitochondrial metabolism has been largely associated with energy production, and its dysfunction is linked to neuronal cell loss. However, the functional role of mitochondria in glial cells has been poorly studied. Recent reports have demonstrated unequivocally that astrocytes do not require mitochondria to meet their bioenergetics demands. Then, the question remaining is, what is the functional role of mitochondria in astrocytes? In this work, we review current evidence demonstrating that mitochondrial central carbon metabolism in astrocytes regulates overall brain bioenergetics, neurotransmitter homeostasis and redox balance. Emphasis is placed in detailing carbon source utilization (glucose and fatty acids), anaplerotic inputs and cataplerotic outputs, as well as carbon shuttles to neurons, which highlight the metabolic specialization of astrocytic mitochondria and its relevance to brain function.

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“…In addition to regulation of glycine abundance, a key activity of the GCS is the provision of glycine-derived one carbon units to folate one-carbon metabolism (FOCM), with downstream flux into nucleotide biosynthesis and methylation reactions. Suppression of FOCM is implicated in the causation of structural malformations in Gldc -deficient embryos, including NTDs and ventriculomegaly ( Leung et al, 2017 ; Santos et al, 2020 ). Hence, these abnormalities can be rescued by provision of additional one-carbon groups to the folate cycle, for example via maternal supplementation with formate ( Pai et al, 2015 ; Leung et al, 2017 ; Santos et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The potential role of GLDC and AMT mutations in some NTDs is supported by the occurrence of NTDs in mouse knockouts of the orthologous genes (Narisawa et al, 2012;Pai et al, 2015;Leung et al, 2017). Among Gldc-deficient mice that are not affected by NTDs, the occurrence of ventriculomegaly and hydrocephalus (resulting from stenosis of the aqueduct of Sylvius) similarly confirm that these are specific effects of GCS-encoding mutations in NKH patients (Autuori et al, 2017;Santos et al, 2020).…”

Section: Introductionmentioning

confidence: 80%

Glycine Cleavage System H Protein Is Essential for Embryonic Viability, Implying Additional Function Beyond the Glycine Cleavage System

et al. 2021

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Glycine cleavage system H protein (GCSH) is a component of the glycine cleavage system (GCS), a conserved protein complex that acts to decarboxylate glycine. Mutation of AMT or GLDC, encoding the GCS components aminomethyltransferase and glycine decarboxylase, can cause malformations of the developing CNS (neural tube defects (NTDs) and ventriculomegaly) as well as a post-natal life-limiting neurometabolic disorder, Non-Ketotic Hyperglycinemia. In contrast, it is unclear whether mutation of GCSH contributes to these conditions and we therefore investigated GCSH loss of function in mice. Mice that were heterozygous for a Gcsh null allele were viable and did not exhibit elevated plasma glycine. Moreover, heterozygous mutation of Gcsh did not increase the frequency of NTDs in Gldc mutant embryos. Homozygous Gcsh null mice were not recovered at post-natal stages. Analysis of litters at E8.5-10.5, revealed the presence of homozygous null embryos which were much smaller than littermates and had failed to develop beyond early post-implantation stages with no visible somites or head-folds. Hence, unlike null mutations of Gldc or Amt, which are compatible with embryonic survival despite the presence of NTDs, loss of Gcsh causes embryonic death prior to mid-gestation. Maternal supplementation with formate did not restore embryonic development beyond E7.5, suggesting that the primary cause of lethality was not loss of glycine cleavage activity or suppression of folate one-carbon metabolism. These findings suggest that GCSH has additional roles beyond function in the glycine cleavage system. We hypothesize that GCSH potentially acts in lipoylation of 2-oxoacid dehydrogenase proteins, as reported in bacteria.

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Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice

Cited by 21 publications

References 36 publications

Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non‐ketotic hyperglycinemia

Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non‐ketotic hyperglycinemia

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

Glycine Cleavage System H Protein Is Essential for Embryonic Viability, Implying Additional Function Beyond the Glycine Cleavage System

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