Kumar, Avadh, Dejanovic, Borislav, Hetsch, Florian, Semtner, Marcus, Fusca, Debora, Arjune, Sita, Santamaria-Araujo, Jose Angel, Winkelmann, Aline, Ayton, Scott ORCID: 0000-0002-3479-2427, Bush, Ashley I., Kloppenburg, Peter, Meier, Jochen C., Schwarz, Guenter ORCID: 0000-0002-2118-9338 and Belaidi, Abdel Ali (2017). S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency. J. Clin. Invest., 127 (12). S. 4365 - 4379. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism characterized by neurodegeneration and death in early childhood. The rapid and progressive neurodegeneration in MoCD presents a major clinical challenge and may relate to the poor understanding of the molecular mechanisms involved. Recently, we reported that treating patients with cyclic pyranopterin monophosphate (cPMP) is a successful therapy for a subset of infants with MoCD and prevents irreversible brain damage. Here, we studied S-sulfocysteine (SSC), a structural analog of glutamate that accumulates in the plasma and urine of patients with MoCD, and demonstrated that it acts as an N-methyl D-aspartate receptor (NMDA-R) agonist, leading to calcium influx and downstream cell signaling events and neurotoxicity. SSC treatment activated the protease calpain, and calpain-dependent degradation of the inhibitory synaptic protein gephyrin subsequently exacerbated SSC-mediated excitotoxicity and promoted loss of GABAergic synapses. Pharmacological blockade of NMDA-R, calcium influx, or calpain activity abolished SSC and glutamate neurotoxicity in primary murine neurons. Finally, the NMDA-R antagonist memantine was protective against the manifestation of symptoms in a tungstate-induced MoCD mouse model. These findings demonstrate that SSC drives excitotoxic neurodegeneration in MoCD and introduce NMDA-R antagonists as potential therapeutics for this fatal disease.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kumar, AvadhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dejanovic, BorislavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hetsch, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semtner, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fusca, DeboraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arjune, SitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santamaria-Araujo, Jose AngelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winkelmann, AlineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ayton, ScottUNSPECIFIEDorcid.org/0000-0002-3479-2427UNSPECIFIED
Bush, Ashley I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloppenburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, Jochen C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, GuenterUNSPECIFIEDorcid.org/0000-0002-2118-9338UNSPECIFIED
Belaidi, Abdel AliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-209287
DOI: 10.1172/JCI89885
Journal or Publication Title: J. Clin. Invest.
Volume: 127
Number: 12
Page Range: S. 4365 - 4379
Date: 2017
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SULFITE OXIDASE DEFICIENCY; BIOLOGICAL FUNCTION; MOLECULAR-BASIS; INBORN-ERRORS; GEPHYRIN; INJURY; METABOLISM; CALCIUM; ENCEPHALOPATHY; DEHYDROGENASEMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20928

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