This confirms a hypothesis that I invoked to explain the results of a study in which I was involved, that examined the role of D-serine in ALS. D-Ser is a co-agonist at the NMDA-R "glycine" site, and is likely to be the most important agonist in the forebrain. However, some evidence had suggested that its overproduction might contribute to excitotoxicity in some instances. John Crow and I crossed the G93A SOD1 mutant mouse with one that lacked the ability to produce D-Ser (though some is still absorbed from food). Expecting the D-Ser reduction to protect from the excitotoxicity that we assumed was contributing to this ALS model, we were surprised to find that the onset of disease was instead hastened. Disease progression was slowed, however, suggesting that excitotoxicity may contribute to pathology in some stages of the disease or in specific neuron populations throughout the course of illness.
References:
Thompson M, Marecki JC, Marinesco S, Labrie V, Roder JC, Barger SW, Crow JP.
Paradoxical roles of serine racemase and d-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis.
J Neurochem. 2012 Feb;120(4):598-610.
PubMed.
Comments
University of Arkansas for Medical Sciences
This confirms a hypothesis that I invoked to explain the results of a study in which I was involved, that examined the role of D-serine in ALS. D-Ser is a co-agonist at the NMDA-R "glycine" site, and is likely to be the most important agonist in the forebrain. However, some evidence had suggested that its overproduction might contribute to excitotoxicity in some instances. John Crow and I crossed the G93A SOD1 mutant mouse with one that lacked the ability to produce D-Ser (though some is still absorbed from food). Expecting the D-Ser reduction to protect from the excitotoxicity that we assumed was contributing to this ALS model, we were surprised to find that the onset of disease was instead hastened. Disease progression was slowed, however, suggesting that excitotoxicity may contribute to pathology in some stages of the disease or in specific neuron populations throughout the course of illness.
References:
Thompson M, Marecki JC, Marinesco S, Labrie V, Roder JC, Barger SW, Crow JP. Paradoxical roles of serine racemase and d-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem. 2012 Feb;120(4):598-610. PubMed.
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