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
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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: |
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Refereed: | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/20928 |
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