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  NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria

Kölker, S., Pawlak, V., Ahlemeyer, B., Okun, J. G., Hörster, F., Mayatepek, E., et al. (2002). NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. European Journal of Neuroscience: European Neuroscience Association, 16(1), 21-28. doi:10.1046/j.1460-9568.2002.02055.x.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-6A17-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-6A18-A
Genre: Journal Article
Alternative Title : NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria

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EurJNeurosci_16_2002_21.pdf (Any fulltext), 298KB
 
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 Creators:
Kölker, Stefan, Author
Pawlak, Verena1, 2, Author              
Ahlemeyer, Barbara, Author
Okun, Jürgen G., Author
Hörster, Friederike, Author
Mayatepek, Ertan, Author
Krieglstein, Josef, Author
Hoffmann, Georg F., Author
Köhr, Georg2, Author              
Affiliations:
1Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              
2Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

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Free keywords: chicken; excitotoxicity; hydroxyglutarate; organic acid disorder; rat
 Abstract: The inherited neurometabolic disease d-2-hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d-2-hydroxyglutarate (D-2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D-2-induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N-methyl-d-aspartate (NMDA) receptor activation. Indeed, D-2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura-2 as a calcium indicator and the oxidant-sensitive dye dihydrorhodamine-123 revealed that D-2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D-2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron-transferring complexes I–IV. Thus, D-2 stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d-2-hydroxyglutaric aciduria, highlighting new neuroprotective strategies.

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Language(s): eng - English
 Dates: 2002-03-062001-12-032002-04-292002-07-112002-07-01
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: European Journal of Neuroscience : European Neuroscience Association
  Other : Eur. J. Neurosci
Source Genre: Journal
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Publ. Info: Oxford, UK : Published on behalf of the European Neuroscience Association by Oxford University Press
Pages: - Volume / Issue: 16 (1) Sequence Number: - Start / End Page: 21 - 28 Identifier: ISSN: 0953-816X
CoNE: https://pure.mpg.de/cone/journals/resource/954925575988