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Molybdenum cofactor deficiency (M°CD) is an autosomal recessive inborn error of metabolism characterized by neurodegeneration and death in early childhood. The rapid and progressive neurodegeneration in M°CD 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 M°CD 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 M°CD, 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 M°CD mouse model. These findings demonstrate that SSC drives excitotoxic neurodegeneration in M°CD and introduce NMDA-R antagonists as potential therapeutics for this fatal disease.
Introduction
Molybdenum cofactor deficiency (M°CD) is a rare metabolic disorder (1, 2) characterized by severe neurological abnormalities including intractable neonatal seizures, feeding difficulties, developmental delay, ocular lens dislocation, and death in early childhood (3). More than 100 cases have been reported (2, 4, 5), the vast majority of which have been characterized by a severe neurological phenotype (6). However, because of a lack of diagnosis or misdiagnosis (7, 8), the global incidence of M°CD is probably underestimated, as the initial neurological symptoms of M°CD resemble a broad spectrum of metabolic and hypoxic encephalopathies (6, 9).
Patients with M°CD harbor mutations in the genes encoding the enzymes molybdenum cofactor synthesis 1 (MOCS1), MOCS2, or gephyrin (GPHN) that are required for molybdenum cofactor (Moco) biogenesis (4, 10), a pathway that is highly conserved throughout evolution. M°CD leads to the loss of activity of 4 molybdenum enzymes in humans (11) including sulfite oxidase (SO). SO is a mitochondrial enzyme (12) that catalyzes the oxidation of toxic sulfite, generated from cysteine metabolism, to sulfate (10). The latter is required for multiple...