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Neurol Res Int. 2012;2012:625245. doi: 10.1155/2012/625245. Epub 2012 Sep 16.

D-Serine Production, Degradation, and Transport in ALS: Critical Role of Methodology.

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1
Department of Pharmacology and Toxicology, The University of Arkansas for Medical Sciences, 325 Jack Stephens Drive, Little Rock, AR 72205, USA ; J. Thomas May Center for ALS Research and Translational Medicine, The University of Arkansas for Medical Sciences, 325 Jack Stephens Drive, Little Rock, AR 72205, USA.

Abstract

In mammalian systems, D-serine is perhaps the most biologically active D-amino acid described to date. D-serine is a coagonist at the NMDA-receptor, and receptor activation is dependent on D-serine binding. Because D-serine binding dramatically increases receptor affinity for glutamate, it can produce excitotoxicity without any change in glutamate per se. D-serine is twofold higher in the spinal cords of mSOD1 (G93A) ALS mice, and the deletion of serine racemase (SR), the enzyme that produces D-serine, results in an earlier onset of symptoms, but with a much slower rate of disease progression. Localization studies within the brain suggest that mSOD1 and subsequent glial activation could contribute to the alterations in SR and D-serine seen in ALS. By also degrading both D-serine and L-serine, SR appears to be a prime bidirectional regulator of free serine levels in vivo. Therefore, accurate and reproducible measurements of D-serine are critical to understanding its regulation by SR. Several methods for measuring D-serine have been employed, and significant issues related to validation and standardization remain unresolved. Further insights into the intracellular transport and tissue-specific compartmentalization of D-serine within the CNS will aid in the understanding of the role of D-serine in the pathogenesis of ALS.

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