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

Autor: Kumar A; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Dejanovic B; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Hetsch F; TU Braunschweig, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany., Semtner M; Cellular Neurosciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Fusca D; Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany., Arjune S; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Santamaria-Araujo JA; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Winkelmann A; TU Braunschweig, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany.; Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany., Ayton S; The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia., Bush AI; The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia., Kloppenburg P; Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany., Meier JC; TU Braunschweig, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany., Schwarz G; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany., Belaidi AA; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2017 Dec 01; Vol. 127 (12), pp. 4365-4378. Date of Electronic Publication: 2017 Nov 06.
DOI: 10.1172/JCI89885
Abstrakt: 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.
Databáze: MEDLINE