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S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency
Avadh Kumar1, Borislav Dejanovic1, Florian Hetsch2
1Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
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.
Insights
S-sulfocysteine (SSC) causes neurotoxicity in molybdenum cofactor deficiency (MoCD) by activating NMDA-receptors and calpain. Blocking these pathways protected against MoCD symptoms in mice, suggesting NMDA-R antagonists as potential therapeutics.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Molybdenum cofactor deficiency (MoCD) is a fatal inherited metabolic disorder causing severe neurodegeneration in infants.
- Understanding MoCD's molecular mechanisms is crucial for developing effective treatments.
- Previous research identified cyclic pyranopterin monophosphate (cPMP) as a therapy for some MoCD patients.
Purpose of the Study:
- To investigate the neurotoxic mechanisms of S-sulfocysteine (SSC) in MoCD.
- To explore the role of N-methyl D-aspartate receptors (NMDA-R) and calpain in MoCD-related neurodegeneration.
- To evaluate NMDA-R antagonists as potential therapeutics for MoCD.
Main Methods:
- Studied SSC's effects on primary murine neurons.
- Investigated SSC's interaction with NMDA-R and calcium influx.
- Assessed the role of calpain activation and gephyrin degradation.
- Utilized a tungstate-induced MoCD mouse model treated with NMDA-R antagonist memantine.
Main Results:
- SSC acts as an NMDA-R agonist, causing calcium influx and neurotoxicity.
- SSC activates calpain, leading to gephyrin degradation and exacerbating excitotoxicity.
- Pharmacological blockade of NMDA-R, calcium, or calpain abolished SSC neurotoxicity in vitro.
- Memantine treatment protected against symptoms in a MoCD mouse model.
Conclusions:
- SSC drives excitotoxic neurodegeneration in MoCD through NMDA-R and calpain pathways.
- NMDA-R antagonists represent a promising therapeutic strategy for MoCD.
- Targeting excitotoxicity offers a novel approach to treating this devastating disease.
