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

摘要: Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism characterized by neurodegeneration and death in early childhood. The rapid progressive MoCD presents a major clinical challenge may relate to the poor understanding molecular mechanisms involved. Recently, we reported that treating patients with cyclic pyranopterin monophosphate (cPMP) successful therapy for subset infants prevents irreversible brain damage. Here, studied S-sulfocysteine (SSC), structural analog glutamate accumulates plasma urine MoCD, demonstrated it acts as N-methyl D-aspartate receptor (NMDA-R) agonist, leading calcium influx downstream cell signaling events neurotoxicity. SSC treatment activated protease calpain, calpain-dependent degradation inhibitory synaptic protein gephyrin subsequently exacerbated SSC-mediated excitotoxicity promoted loss GABAergic synapses. Pharmacological blockade NMDA-R, influx, or calpain activity abolished neurotoxicity primary murine neurons. Finally, NMDA-R antagonist memantine was protective against manifestation symptoms tungstate-induced mouse model. These findings demonstrate drives excitotoxic introduce antagonists potential therapeutics this fatal disease.