title: Paradoxical roles of serine racemase and D-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis.
abstract: D-serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of D-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of D-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by D-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades D-serine as well. D-serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice--the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of D-serine to ALS mice dramatically lowers cord levels of D-serine, leading to changes in the onset and survival very similar to SR deletion. D-serine treatment also increases cord levels of the alanine-serine-cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases D-serine is not known, these results strongly suggest that SR and D-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
authors: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors: Misty
authors: M
authors: Thompson
authors: John C
authors: JC
authors: Marecki
authors: Stephane
authors: S
authors: Marinesco
authors: Viviane
authors: V
authors: Labrie
authors: John C
authors: JC
authors: Roder
authors: Steven W
authors: SW
authors: Barger
authors: John P
authors: JP
authors: Crow
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019998:Racemases and Epimerases / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D012694:Serine / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000235:genetics; D000099300:Serine Racemase
chemical_list: D019998:Racemases and Epimerases; D012694:Serine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099300:Serine Racemase; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse