- The EMBO Journal (2007) 26, 4149 - 4159
Published online: 30 August 2007
D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis
- Department of Anatomy, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
- Department of Cell Biology and Neuroscience, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
- Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
Masaaki Matsuoka, Department of Cell Biology and Neuroscience/Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 8427; Fax: +81 3 5363 8428; E-mail: firstname.lastname@example.org
aTo our regret, he passed away on 17 October 2003.
Received 8 March 2007; Accepted 30 July 2007
Excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). More recently, glial involvement has been shown to be essential for ALS-related motoneuronal death. Here, we identified an N-methyl-D-aspartate (NMDA) receptor co-agonist, D-serine (D-Ser), as a glia-derived enhancer of glutamate (Glu) toxicity to ALS motoneurons. Cell death assay indicated that primary spinal cord neurons from ALS mice were more vulnerable to NMDA toxicity than those from control mice, in a D-Ser-dependent manner. Levels of D-Ser and its producing enzyme, serine racemase, in spinal cords of ALS mice were progressively elevated, dominantly in glia, with disease progression. In vitro, expression of serine racemase was induced not only by an extracellular pro-inflammatory factor, but also by transiently expressed G93A-superoxide dismutase1 in microglial cells. Furthermore, increases of D-Ser levels were also observed in spinal cords of both familial and sporadic ALS patients. Collectively, Glu toxicity enhanced by D-Ser overproduced in glia is proposed as a novel mechanism underlying ALS motoneuronal death, and this mechanism may be regarded as a potential therapeutic target for ALS.
IntroductionTop of page
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, pathologically characterized by massive selective motoneuronal loss, inclusion bodies in remaining neurons and astrocytes, and gliosis around dying neurons in the ventral horns of spinal cords (Bruijn et al, 2004). Approximately 90% of ALS cases are sporadic, while 10% are inherited. About 20% of inherited cases have mutations in the gene encoding superoxide dismutase 1 (SOD1) (Rosen et al, 1993). Although the discovery of mutations in SOD1 has resulted in a considerable number of studies, the mechanism of selective motoneuronal death is still unclear. Among several proposed hypotheses on the pathogenesis of ALS, excitotoxicity mediated by ionotropic glutamate (Glu) receptors has been regarded as a principal cause of motoneuronal death (Bruijn et al, 2004; Van Damme et al, 2005). This notion was supported by the fact that a three-fold increase in the Glu level was detected in the cerebrospinal fluid of patients with ALS due to loss of Glu uptake by astrocytes (Rothstein et al, 1990, 1995) and that an inhibitor of Glu release, Riluzole, is the sole drug clinically effective against ALS. The former observation was confirmed by a cohort study indicating that the Glu level increased in the cerebrospinal fluid of 40% of sporadic ALS patients (Spreux-Varoquaux et al, 2002). Together with the finding that the loss of Glu transporters was detected in ALS model rats with a SOD1 mutant (Howland et al, 2002), it seems most likely that Glu toxicity has some important roles in the pathogenesis of both inherited and sporadic ALS. However, the detailed mechanisms underlying Glu toxicity on motoneurons still remain elusive.
There are three classes of ionotropic Glu receptors: N-methyl-D-aspartate receptors (NMDARs), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and kainate receptors (Van Damme et al, 2005). The AMPA receptors have been assumed to play a central role in ALS-relevant Glu toxicity, because a defect in the editing of mRNA encoding GluR2, which resulted in increased Ca2+ influx, was found in patients with sporadic ALS (Kawahara et al, 2004). At the same time, the NMDARs have been shown in vitro to be as important as the AMPA receptors for Glu toxicity in neurons (Prehn et al, 1995). A more recent finding shed light on the relevance of the NMDARs in ALS pathogenesis: an NMDAR antagonist, memantine, has been reported to prolong survival in ALS model mice (Wang and Zhang, 2005). Activation of the NMDARs essentially requires the binding of a co-agonist to its glycine site. D-Serine (D-Ser) is a physiologically dominant excitotoxic co-agonist to the glycine site compared with glycine (Shleper et al, 2005; Panatier et al, 2006), and is endogenously converted from L-serine (L-Ser) by serine racemase (SRR). SRR is mainly expressed in glia (Wolosker et al, 1999a) and upregulated by glial activation (Wu and Barger, 2004; Wu et al, 2004). Considering that insults generated from activated glia are assumed to be essential for the induction of motoneuronal death (Pramatarova et al, 2001; Clement et al, 2003; Boillee et al, 2006), we hypothesized that in ALS, the excessive amounts of D-Ser generated from the activated glia may contribute to the development of Glu toxicity. In the present study, we demonstrate evidence supporting this hypothesis.http://www.39kf.com/uploadfiles/image/15821/TXT-2008122865848214.gif