S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency
Avadh Kumar, … , Guenter Schwarz, Abdel Ali Belaidi
Avadh Kumar, … , Guenter Schwarz, Abdel Ali Belaidi
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4365-4378. https://doi.org/10.1172/JCI89885.
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Research Article Neuroscience

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

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.

Authors

Avadh Kumar, Borislav Dejanovic, Florian Hetsch, Marcus Semtner, Debora Fusca, Sita Arjune, Jose Angel Santamaria-Araujo, Aline Winkelmann, Scott Ayton, Ashley I. Bush, Peter Kloppenburg, Jochen C. Meier, Guenter Schwarz, Abdel Ali Belaidi

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Figure 2

SSC, not sulfite, evokes somatic membrane currents and depolarizes the neuronal membrane potential.

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SSC, not sulfite, evokes somatic membrane currents and depolarizes the n...
(A) Current traces of hippocampal neurons at –50 mV in the presence of 0.3 μM TTX and 100 μM sulfite, SSC, or glutamate. (B) Quantification of current amplitudes under basal conditions and in the presence of 100 μM sulfite, 100 μM SSC, or 100 μM glutamate. (C) NMDA-R antagonists markedly decreased SSC-evoked current amplitudes in hippocampal neurons. (D) Quantification of the percentage of inhibition of tonic SSC–evoked currents by NMDA-R antagonists. Current amplitudes in the presence of 10 μM MK801 or 50 μM APV were normalized to SSC-induced current peaks. (E) Application of both APV and DNQX almost completely blocked SSC-elicited currents. (F) Quantification of the additive effect of NMDA-R and AMPA-R blocker on current amplitudes. Data are presented as the mean ± SEM. Numbers in parentheses in B, D, and F indicate the number of recorded neurons. *P < 0.05 and ***P < 0.001, by 1-way ANOVA with Tukey’s multiple comparisons test.