Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation

Ravasz, Dora; Kacso, Gergely; Fodor, Viktoria; Horvath, Kata; Ádám-Vizi, Vera; Chinopoulos, Christos

doi:10.1016/j.neuint.2017.03.008

Cited by 37 publications

(33 citation statements)

References 101 publications

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“…Additionally, some mutations in ABAT can express residual enzymatic activity and not a complete ablation of enzymatic activity resulting in “partial” decreases in metabolites downstream of ABAT (Pop et al, 2015). As succinate also is formed downstream of ABAT activity, and it is involved in mitochondrial physiology, a diagnosis of GABA-transaminase deficiency needs to be differentiated from mitochondrial diseases due to mutations in mitochondrial DNA (Besse et al, 2015) or other aspects of mitochondrial physiology (Ravasz et al, 2017). Building panels of biomarkers specific for an increasing number of diverse diseases can help to further increase the utility of biochemical phenotyping as a screening technology.…”

Section: Discussionmentioning

confidence: 99%

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

et al. 2019

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Broad-scale untargeted biochemical phenotyping is a technology that supplements widely accepted assays, such as organic acid, amino acid, and acylcarnitine analyses typically utilized for the diagnosis of inborn errors of metabolism. In this study, we investigate the analyte changes associated with 4-aminobutyrate aminotransferase (ABAT, GABA transaminase) deficiency and treatments that affect GABA metabolism. GABA-transaminase deficiency is a rare neurodevelopmental and neurometabolic disorder caused by mutations in ABAT and resulting in accumulation of GABA in the cerebrospinal fluid (CSF). For that reason, measurement of GABA in CSF is currently the primary approach to diagnosis. GABA-transaminase deficiency results in severe developmental delay with intellectual disability, seizures, and movement disorder, and is often associated with death in childhood. Using an untargeted metabolomics platform, we analyzed EDTA plasma, urine, and CSF specimens from four individuals with GABA-transaminase deficiency to identify biomarkers by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort. Metabolomic analyses of over 1,000 clinical plasma samples revealed a rich source of biochemical information. Three out of four patients showed significantly elevated levels of the molecule 2-pyrrolidinone ( Z -score ≥ 2) in plasma, and whole exome sequencing revealed variants of uncertain significance in ABAT . Additionally, these same patients also had elevated levels of succinimide or its ring-opened form, succinamic acid, in plasma, urine, and CSF and/or homocarnosine in urine and CSF. In the analysis of clinical EDTA plasma samples, the levels of succinamic acid and 2-pyrrolidinone showed a high level of correlation ( R = 0.72), indicating impairment in GABA metabolism and further supporting the association with GABA-transaminase deficiency and the pathogenicity of the ABAT variants. Further analysis of metabolomic data across our patient population revealed the association of elevated levels of 2-pyrrolidinone with administration of vigabatrin, a commonly used anti-seizure medication and a known inhibitor of GABA-transaminase. These data indicate that anti-seizure medications may alter the biochemical and metabolomic data, potentially impacting the interpretation and diagnosis for the patient. Further, these data demonstrate the power of combining broad scale genotyping and phenotyping technologies to diagnose inherited neurometabolic disorders and support the use of metabolic phenotyping of plasma to screen for GABA-transaminase deficiency.

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Section: Discussionmentioning

confidence: 99%

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

et al. 2019

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“…iGABASnFR imaging in appropriate animal models will facilitate greater understanding of these mechanisms. iGABASnFR could also allow easy screening 67 of candidate transporters such as the vertebrate mitochondrial GABA transporter 27 . Applications outside of neuroscience are also possible, such as separating the critical roles of GABA in plant metabolism and signaling 68 .…”

Section: Discussionmentioning

confidence: 99%

“…After being transported into mitochondria (by an as yet unidentified transporter 27 ), GABA is degraded by GABA transaminase (GABA-T). Inhibition of GABA-T elevates synaptic levels of GABA 28 and, of clinical significance, the GABA-T inhibitor vigabatrin is a currently prescribed antiepileptic 29 .…”

Section: Gaba Processing In Mitochondriamentioning

confidence: 99%

A genetically encoded fluorescent sensor for in vivo imaging of GABA

Marvin

Shimoda

Malgoire

et al. 2018

Preprint

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Protein engineering and experiment design: JSM, LLL Hippocampal slice imaging: TPJ, DAR Visual cortex volume imaging: KP, ON Mouse epilepsy model: YS, VM, ML, DMK Mitochondria experiments: ELK, NJL Zebrafish: TK, MBA Abstract (150 words)Current techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR (∆F/Fmax ~ 2.5, Kd ~ 9 µM, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of: (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.

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“…GABA-T hydrolyses GABA. Mature GABA is first deaminated by GABA-T to form succinic semialdehyde (SSA); SSA is then converted to succinic acid, (catalyzed by succinate semialdehyde dehydrogenase), and the end product (succinic acid) then enters the tricarboxylic acid cycle to form Glu once again (16,(40)(41)(42). It is therefore evident that the activities of GAD and GABA-T can directly influence the levels of GABA and Glu.…”

Section: Discussionmentioning

confidence: 99%

Schisandrin B exerts hypnotic effects in PCPA‑treated rats by increasing hypothalamic 5‑HT and γ‑aminobutyric acid levels

Wang

Shu

et al. 2020

Exp Ther Med

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Schisandrin B (SchB) is one of the primary active components of Schisandra chinensis (Turcz.) Baill., a traditional Chinese herb that has been used to treat insomnia for hundreds of years. Our previous studies revealed that SchB exerts sedative and hypnotic effects, increasing the content of γ-aminobutyric acid (GABA) and the expression of its receptors in the brain tissues of rats. 5-hydroxytryptamine (5-HT) is another important neurotransmitter involved in sleep regulation, although, to the best of our knowledge, there are no reports of its association with SchB. Therefore, the present study aimed to determine whether the hypnotic effect of SchB was partly due to alterations in the expression of 5-HT. The results indicated that SchB reduced sleep latency and increased sleep duration in parachlorophenylalanine (PCPA)-induced rats with insomnia by increasing 5-HT and 5-hydroxyindoleacetic acid, and upregulating the expression of the 5-HT receptor 1A in the hypothalamus. SchB also increased the ratio of GABA to glutamic acid and the activity of glutamic acid decarboxylase, decreased the activity of GABA transaminase, and upregulated the expression of GABA A receptor α1 and GABA A receptor γ2 in the rat hypothalamus. These results suggested that SchB improved PCPA-induced insomnia in rats, and its effects may be associated with the regulation of GABA and 5-HT levels in the hypothalamus.

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Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation

Cited by 37 publications

References 101 publications

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

A genetically encoded fluorescent sensor for in vivo imaging of GABA

Schisandrin B exerts hypnotic effects in PCPA‑treated rats by increasing hypothalamic 5‑HT and γ‑aminobutyric acid levels

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Catabolism of GABA, succinic semialdehyde or gamma-hydroxybutyrate through the GABA shunt impair mitochondrial substrate-level phosphorylation

Cited by 37 publications

References 101 publications

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

A genetically encoded fluorescent sensor for in vivo imaging of GABA

Schisandrin B exerts hypnotic effects in PCPA‑treated rats by increasing hypothalamic 5‑HT and &gamma;‑aminobutyric acid levels

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Schisandrin B exerts hypnotic effects in PCPA‑treated rats by increasing hypothalamic 5‑HT and γ‑aminobutyric acid levels