d-Amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes

Horiike, Kihachiro; Tojo, Hiromasa; Arai, Ryohachi; Nozaki, Mitsuhiro; Maeda, Toshihiro

doi:10.1016/0006-8993(94)90240-2

Cited by 156 publications

(112 citation statements)

References 36 publications

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“…Based on this finding, the fluorescence derived from KYNA produced enzymatically from D-KYN by DAAO was calculated by subtracting the fluorescence value without the pellet fraction (blank) from the sample fluorescence intensity at 396 nm. As might be expected, DAAO activity expressed as fmol KYNA/min/μg protein was the highest in rat cerebellum, followed by brain stem and cerebrum (Figure 4), in agreement with previous reports (26,27).…”

Section: Real-time Quantitative Pcrsupporting

confidence: 93%

Fluorimetric assay for D-amino acid oxidase activity in rat brain homogenate by using D-kynurenine as a substrate

Kozaki¹

2012

Biosci Trends

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Section: Real-time Quantitative Pcrsupporting

confidence: 93%

Fluorimetric assay for D-amino acid oxidase activity in rat brain homogenate by using D-kynurenine as a substrate

Kozaki¹

2012

Biosci Trends

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“…In rat brains, the localization of D-amino acid oxidase activity is reciprocal to that of D-serine (8,9), suggesting that D-amino acid oxidase determines the basal levels of D-serine in mammalian brains. However, we have found recently that, in the chicken brain, D-serine is degraded mainly by a D-serine dehydratase (DSD) 4 (10), which catalyzes the ␣,␤-elimination of water from D-serine to form pyruvate and ammonia.…”

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confidence: 99%

Crystal Structure of a Zinc-dependent d-Serine Dehydratase from Chicken Kidney

Tanaka

Senda

Venugopalan

et al. 2011

Journal of Biological Chemistry

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D-Serine is a co-agonist of the NMDA receptor, an excitatory neurotransmitter receptor important for higher brain functions, including learning and memory (1, 2). The NMDA receptor is a glutamate-gated ion channel (3), and glutamate does not activate the receptor unless a co-agonist binding site is simultaneously occupied by D-serine or glycine (4). Because significant concentrations of D-serine exist in vertebrate brains (5), D-serine is believed to physiologically control the sensitivity of the NMDA receptor to glutamate (6).In mammals, D-serine is produced by a bifunctional serine racemase/dehydratase (7) and is mainly degraded by D-amino acid oxidase (2, 7). In rat brains, the localization of D-amino acid oxidase activity is reciprocal to that of D-serine (8, 9), suggesting that D-amino acid oxidase determines the basal levels of D-serine in mammalian brains. However, we have found recently that, in the chicken brain, D-serine is degraded mainly by a D-serine dehydratase (DSD) 4 (10), which catalyzes the ␣,␤-elimination of water from D-serine to form pyruvate and ammonia. In addition, we have found that the chicken DSD (chDSD) has a primary structure similar to those of metal-activated D-threonine aldolases (11-13), which are fold-type III PLP-dependent enzymes (14), and is distinct from a well known metal-independent bacterial DSD (dsdA) belonging to the foldtype II PLP-dependent enzyme family (14,15). Interestingly, a fold-type III family protein coded by gene YGL196W of Saccharomyces cerevisiae was recently identified as a zinc-dependent DSD (scDSD) (16). To understand why avian species use DSD to metabolize D-serine in the brain and its physiological functions, it is important to reveal the structural and enzymatic properties of this novel DSD family.In the present study, we showed that chDSD requires Zn 2ϩ just as scDSD does. Then, to reveal the catalytic roles of Zn 2ϩ in the dehydration of D-serine, we determined the crystal structures of chDSD, EDTA-treated chDSD, and the EDTA-treated chDSD⅐D-serine complex. Although there is only one DSD entry in the Protein Data Bank (PDB), DSD from Burkholderia xenovorans LB400 (PDB code 3GWQ), the structure contains neither PLP nor zinc, and the enzymatic properties of this DSD *

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“…To elucidate the pathophysiological significance of DAO in ALS, we visualized DAO activity in cryostat sections by modifying an enzyme histochemical (EHC) technique for vibratome sections (15). EHC is based on oxidation of diaminobenzidine with peroxidase by using D-proline as a substrate of DAO.…”

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confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/ familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.excitotoxicity | motor neuron disease | neurodegeneration | enzyme histochemistry | 2D-HPLC A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1, 2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated.The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca ...

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d-Amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes

Cited by 156 publications

References 36 publications

Fluorimetric assay for D-amino acid oxidase activity in rat brain homogenate by using D-kynurenine as a substrate

Fluorimetric assay for D-amino acid oxidase activity in rat brain homogenate by using D-kynurenine as a substrate

Crystal Structure of a Zinc-dependent d-Serine Dehydratase from Chicken Kidney

d -Amino acid oxidase controls motoneuron degeneration through d -serine

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