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| Item Type: | Article |
|---|---|
| Title: | S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency |
| Creators Name: | Kumar, A., Dejanovic, B., Hetsch, F., Semtner, M., Fusca, D., Arjune, S., Santamaria-Araujo, J.A., Winkelmann, A., Ayton, S., Bush, A.I., Kloppenburg, P., Meier, J.C., Schwarz, G. and Belaidi, A.A. |
| 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. |
| Keywords: | Animal Disease Models, Calcium Signaling, Cysteine, GABAergic Neurons, HEK293 Cells, Inborn Errors Metal Metabolism, Memantine, N-Methyl-D-Aspartate Receptors, Neurodegenerative Diseases, Organophosphorus Compounds, Pterins, Synapses, Tungsten Compounds, Animals, Mice |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 127 |
| Number: | 12 |
| Page Range: | 4365-4378 |
| Date: | 1 December 2017 |
| Additional Information: | Copyright © 2017, American Society for Clinical Investigation |
| Official Publication: | https://doi.org/10.1172/JCI89885 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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