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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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 5

Induction of MoCD in mice prompts SSC formation and neuronal cell death.

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Induction of MoCD in mice prompts SSC formation and neuronal cell death....
(A) Liver SO activity in mice after 4 weeks of treatment (n = 7/group). (B) Assessment of body weights (n = 32 mice/treatment group) of male and female mice. (C) SSC accumulation in urine (n = 7 control mice, n = 9 tungsten-treated mice). (D) Normalized SSC levels in extracts of brain (black circles and white squares represent 2 individual mice cohorts; n = 12 control, n = 13 SSC) and liver (n = 7 control, n = 6 SSC). (E) Calculated SSC concentration in brain extracts from D (n = 12 control, n = 13 SSC). (E and F) Immunoblots showing the expression of gephyrin and spectrin in brain and liver extracts (E) and the expression of PSD95 in brain extracts (F) from control and tungsten-treated mice (n = 4/group). (G) Nissl-stained images of brain sections from control and tungsten-treated mice, with representative sections of cortical and hippocampal regions and quantification of neuronal density and size in cortex (layers 1 and 2) and hippocampal CA1 regions (n= 32 cortex, n = 18 CA1, derived from 3 mice/group). Scale bar: 200 μm. Data are presented as the mean ± the SEM. Red lines indicate the median value. **P < 0.01 and ***P < 0.001, by 2-way ANOVA with Dunnett’s multiple comparisons test (A), 2-tailed, unpaired Student’s t test (B and C), 1-way ANOVA with Tukey’s multiple comparisons test (D), or 2-tailed, paired Student’s t test (G).