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. © 2011 International Society for Neurochemistry.