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Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism

Hull, Jonathon; Usmari Moraes, Marcela; Brookes, Emma; Love, Seth; Conway, Myra E.

Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism Thumbnail


Authors

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Jonathon Hull Jonathon2.Hull@uwe.ac.uk
Senior Lecturer in Biomedical Sci (Biochemistry)

Marcela Usmari Moraes

Emma Brookes

Seth Love

Myra Conway Myra.Conway@uwe.ac.uk
Occasional Associate Lecturer - CHSS - DAS



Abstract

© 2017 Glutamate is the major excitatory neurotransmitter of the central nervous system, with the branched-chain amino acids (BCAAs) acting as key nitrogen donors for de novo glutamate synthesis. Despite the importance of these major metabolites, their metabolic pathway in the human brain is still not well characterised. The metabolic pathways that influence the metabolism of BCAAs have been well characterised in rat models. However, the expression of key proteins such as the branched-chain α-ketoacid dehydrogenase (BCKD) complex and glutamate dehydrogenase isozymes (GDH) in the human brain is still not well characterised. We have used specific antibodies to these proteins to analyse their distribution within the human brain and report, for the first time, that the E1α subunit of the BCKD is located in both neurons and vascular endothelial cells. We also demonstrate that GDH is localised to astrocytes, although vascular immunolabelling does occur. The labelling of GDH was most intense in astrocytes adjacent to the hippocampus, in keeping with glutamatergic neurotransmission in this region. GDH was also present in astrocyte processes abutting vascular endothelial cells. Previously, we demonstrated that the branched-chain aminotransferase (hBCAT) proteins were most abundant in vascular cells (hBCATm) and neurons (hBCATc). Present findings are further evidence that BCAAs are metabolised within both the vasculature and neurons in the human brain. We suggest that GDH, hBCAT and the BCKD proteins operate in conjunction with astrocytic glutamate transporters and glutamine synthetase to regulate the availability of glutamate. This has important implications given that the dysregulation of glutamate metabolism, leading to glutamate excitotoxicity, is an important contributor to the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease.

Citation

Hull, J., Usmari Moraes, M., Brookes, E., Love, S., & Conway, M. E. (2018). Distribution of the branched-chain α-ketoacid dehydrogenase complex E1α subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism. Neurochemistry International, 112, 49-58. https://doi.org/10.1016/j.neuint.2017.10.014

Journal Article Type Article
Acceptance Date Nov 13, 2017
Online Publication Date Nov 2, 2017
Publication Date Jan 1, 2018
Deposit Date Nov 17, 2017
Publicly Available Date Mar 29, 2024
Journal Neurochemistry International
Print ISSN 0197-0186
Electronic ISSN 1872-9754
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 112
Pages 49-58
DOI https://doi.org/10.1016/j.neuint.2017.10.014
Keywords BCAA, BCKD, GDH, glutamate
Public URL https://uwe-repository.worktribe.com/output/871871
Publisher URL http://dx.doi.org/10.1016/j.neuint.2017.10.014

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