We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency.
- Authors
Kumar, Avadh; Dejanovic, Borislav; Arjune, Sita; Santamaria-Araujo, Jose Angel; Belaidi, Abdel Ali; Schwarz, Guenter; Hetsch, Florian; Meier, Jochen C.; Winkelmann, Aline; Semtner, Marcus; Fusca, Debora; Kloppenburg, Peter; Ayton, Scott; Bush, Ashley I.
- 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.
- Subjects
MOLYBDENUM cofactor deficiency; NEURODEGENERATION; METHYL aspartate receptors; CYSTEINE; GEPHYRIN; INFANT diseases; GENETICS
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 12, p4365
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI89885