Potential pathophysiological role of D-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain.
D-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of D-amino acids. Among the possible substrates of DAO in vivo, D-serine is proposed to be a neuromodulator of the N-methyl-D-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant D-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate D-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia.
Ono
Koji
K
Division of Enzyme Pathophysiology, The Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
Shishido
Yuji
Y
Park
Hwan Ki
HK
Kawazoe
Tomoya
T
Iwana
Sanae
S
Chung
Seong Pil
SP
Abou El-Magd
Rabab M
RM
Yorita
Kazuko
K
Okano
Mai
M
Watanabe
Takeshi
T
Sano
Nobuya
N
Bando
Yoshimi
Y
Arima
Kunimasa
K
Sakai
Takashi
T
Fukui
Kiyoshi
K
D000368:Aged; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D002831:Choroid Plexus / Q000201:enzymology / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009457:Neuroglia / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000201:enzymology* / Q000378:metabolism*; D013045:Species Specificity
D012333:RNA, Messenger; D003605:D-Amino-Acid Oxidase
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3089-93
10716694
Schizophr Res. 2008 Apr;101(1-3):76-83
18378121
Biochem Biophys Res Commun. 2007 Apr 6;355(2):385-91
17303072
Gene. 1990 Jun 15;90(2):293-7
1976103
Cell. 1999 Aug 20;98(4):427-36
10481908
Biol Psychiatry. 2005 Mar 15;57(6):577-85
15780844
Eur J Neurosci. 2007 Sep;26(6):1657-69
17880399
Brain Res. 1994 Aug 1;652(2):297-303
7953743
Adv Drug Deliv Rev. 2004 Oct 14;56(12):1695-716
15381330
J Psychopharmacol. 2010 Jul;24(7):1055-67
19329549
FEBS Lett. 1992 Jan 13;296(1):33-6
1730289
Biol Psychiatry. 1998 Dec 1;44(11):1081-9
9836012
Nucleic Acids Res. 1990 Sep 11;18(17):5322
1698283
Arch Gen Psychiatry. 2003 Jun;60(6):572-6
12796220
Proc Natl Acad Sci U S A. 1989 Mar;86(5):1684-8
2784211
Protein Sci. 2006 Dec;15(12):2708-17
17088322
J Neurocytol. 1999 Mar;28(3):169-85
10617900
J Enzyme Inhib Med Chem. 2008 Dec;23(6):901-11
18615285
Biochem J. 1935 Jul;29(7):1620-44
16745832
Biochemistry. 1987 Jun 16;26(12):3612-8
2888479
J Neurochem. 1973 Oct;21(4):1037-9
4148237
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3948-52
7732010
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Dec 12;32(8):1905-12
18835577
Biochemistry. 1988 Sep 6;27(18):6693-7
2904274
J Biochem. 1990 Sep;108(3):406-13
1980495
Biol Psychiatry. 2005 Jun 15;57(12):1493-503
15953485
J Biol Chem. 1994 Dec 16;269(50):31666-73
7989339
Nucl Med Biol. 2005 Nov;32(8):793-7
16253803
Schizophr Res. 2007 Feb;90(1-3):41-51
17156977
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4926-31
10781100
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jun;29(5):767-9
15939521
Chem Rec. 2007;7(5):305-15
17924443
Brain Res Bull. 1987 Nov;19(5):587-96
2891417
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13675-80
12364586
J Biochem. 2006 Feb;139(2):295-304
16452318
Neurosci Lett. 2002 May 17;324(2):101-4
11988337
J Neurochem. 1997 Sep;69(3):1286-90
9282954
FEBS Lett. 1988 Sep 26;238(1):180-4
2901986
FEBS Lett. 1988 Oct 10;238(2):269-72
2901989
Biol Pharm Bull. 2005 Sep;28(9):1561-5
16141516
Adv Drug Deliv Rev. 2004 Oct 14;56(12):1717-40
15381331