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S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

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Item Type:Article
Title:S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency
Creators Name:Kumar, A. and Dejanovic, B. and Hetsch, F. and Semtner, M. and Fusca, D. and Arjune, S. and Santamaria-Araujo, J.A. and Winkelmann, A. and Ayton, S. and Bush, A.I. and Kloppenburg, P. and Meier, J.C. and 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
Publisher:American Society for Clinical Investigation
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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