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Serine Racemase Binds to PICK1: Potential Relevance to Schizophrenia

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Serine Racemase Binds to PICK1: Potential Relevance to Schizophrenia Molecular Psychiatry (2006) 11, 150–157 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp ORIGINAL ARTICLE Serine racemase binds to PICK1: potential relevance to schizophrenia K Fujii1,2,8, K Maeda1,3,8, T Hikida4,9, AK Mustafa4,9, R Balkissoon1,9, J Xia4, T Yamada3, Y Ozeki1,2, R Kawahara3, M Okawa2, RL Huganir2,5, H Ujike6, SH Snyder1,4,5,7 and A Sawa1,4,5 1Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan; 3Division of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Japan; 4Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan and 7Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ). Although an association of genes for D-serine degradation, such as D-amino acid oxidase and G72, has been reported, a role for D-serine in SZ has been unclear. In this study, we identify and characterize protein interacting with C-kinase (PICK1) as a protein interactor of the D-serine synthesizing enzyme, serine racemase (SR). The binding of endogenous PICK1 and SR requires the PDZ domain of PICK1. The gene coding for PICK1 is located at chromosome 22q13, a region frequently linked to SZ. In a case–control association study using well-characterized Japanese subjects, we observe an association of the PICK1 gene with SZ, which is more prominent in disorganized SZ. Our findings implicating PICK1 as a susceptibility gene for SZ are consistent with a role for D-serine in the disease. Molecular Psychiatry (2006) 11, 150–157. doi:10.1038/sj.mp.4001776; published online 29 November 2005 Keywords: schizophrenia; PICK1; serine racemase; D-serine; yeast two-hybrid; case–control study Introduction Genetic association studies also implicate D-serine in SZ. In several independent studies, genes coding Glutamate neurotransmission has been implicated in for the D-serine degrading enzyme, D-amino acid schizophrenia (SZ).1–5 Activation of NMDA receptors oxidase (DAO), and its potential regulator G72, are requires stimulation of a glycine site in addition to the associated with SZ.21–27 6 glutamate recognition site. Recent studies establish We have explored a role for D-serine synthesis in D-serine as an endogenous ligand for this site in many SZ. As the gene for SR itself is located to chromosome areas of the brain, while glycine itself may be the 17, which has been neither linked to nor associated endogenous ligand in certain regions.7–13 D-serine is with SZ,28 we focused on binding partners for SR with generated from L-serine by the enzyme serine race- some relationship to SZ. Here, we report binding of mase (SR) that is localized to a population of glial SR to protein interacting with C-kinase (PICK1), astrocytes, which ensheathe synapses in brain regions whose gene is located at chromosome 22q13.1. The enriched in NMDA receptors.14,15 Glutamate released chromosome 22q11–13 region displays linkage to from neurons activates glutamate receptors of the SZ,29–34 and a cluster of genes in the region are AMPA subtype on these astrocytes triggering the associated with SZ, including catechol-O-methyl- release of D-serine.7 Treatment of SZ with D-serine, transferase,35,36 ZDHHC8,37 and proline dehydrogen- D-cycloserine, or glycine together with classic neuro- ase.38–40 We also demonstrate an association of the leptics ameliorates some symptoms.16–20 PICK1 gene with disorganized SZ. Correspondence: Dr A Sawa, Department of Psychiatry, Johns Materials and methods Hopkins University School of Medicine, 600 North Wolfe St, Baltimore, MD 21287, USA. Yeast two-hybrid screening E-mail: [email protected] Yeast two-hybrid screening was performed using a 8These authors contributed equally to the work. 9These authors contributed equally to the work. human adult whole brain cDNA library subcloned Received 13 April 2005; revised 7 September 2005; accepted 4 into the pPC86 vector, which contains the GAL4 October 2005; published online 29 November 2005 transactivation domain.41 The bait was the full length PICK1 and schizophrenia K Fujii et al 151 of human SR subcloned into pDBlue vector, which follows: a polyclonal rabbit anti-HA antibody (Medi- contains the GAL4 DNA binding domain. Over one cal and Biological Laboratories) and a monoclonal million independent clones were screened, and mouse anti-myc antibody (Calbiochem), which are positively interacting proteins were identified by commercially available as specific antibodies. Sec- selecting for Leu þ , Trip þ , His þ growth phenotype. ondary antibodies used for fluorescence were follows: Positive clones were further evaluated for b-galacto- a Rhodamine Red-X conjugated anti-rabbit IgG anti- sidase expression. All of the constructs were from body and a cyanine Cy2 conjugated anti-mouse PCR products subcloned in frame into pPC86 or antibody (Jackson ImmunoResearch). pDBlue vectors and were confirmed by sequencing. PICK1 K27A/D28A mutant was generated as des- Subjects in association study cribed previously.42 The subjects in the present case–control association study were 200 unrelated Japanese SZ patients (108 Cell culture and transfection men and 92 women; mean age 46.379.9 years) Cultured astrocytes were prepared from the cerebral fulfilling the international statistical classification of cortex of 2- to 6-day-old postnatal mice as described.43 the disease, revision 10 (ICD-10) diagnostic criteria for Cultured astrocytes and HEK293 cells were main- SZ, and 200 age-matched Japanese normal controls tained in DMEM media supplemented with 2 mML- (91 men and 109 women; mean age 43.3710.9 years) glutamine and 10% fetal bovine serum. Transfection who had no positive personal or familial history of of hemagglutinin (HA)-tagged SR and/or myc-tagged major psychiatric disorders. Patients in this study PICK1 was carried out by calcium phosphate method. retained their diagnosis by the ICD-10 for at least 3 years indicating a high reliability of their initial In vitro binding assay diagnosis. Trained psychiatrists who did not partici- PICK1, PICK1 mutants or GAPDH was fused to pate in the genetic association study diagnosed glutathione-S-transferase (GST) by subcloning into a patients. Population stratification was discussed in pGEX vector (Amersham Biosciences). Extracts of the previous studies using the same sample set.44,45 Escherichia coli strain BL21 were used as a source of For further analysis, the SZ patients were subdivided GST fusion proteins. Lysates of HEK293 cells tran- into 90 patients of disorganized type and 110 of siently transfected with a HA-tagged SR cDNA and nondisorganized type according to the criteria set out purified GST-fusion protein were incubated in 50 mM in the Diagnostic and Statistical Manual of Mental Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM phenylmethane Disorders, Fourth Edition (DSM-IV). Disorganized sulfonylfluoride (PMSF), and 1 mM 1,4-dithiothreitol, type (DSM-IV: 295.10) were previously diagnosed as and a protease inhibitor mixture (Roche) for 45 min. hebephrenic type (ICD-10: F20.1), and nondisorga- HA-tagged SR bound to GST-fusion protein was nized type as paranoid (F20.0), catatonic (F20.2), or precipitated with glutathione sepharose beads (Amer- undifferentiated type (F20.3), respectively.44,45 Asses- sham Biosciences). The protein precipitates were sment for diagnosis and subtype of SZ were per- analysed with SDS-PAGE, followed by Western blot- formed by trained psychiatrists who did not partici- ting with a polyclonal antibody against HA (Medical pate in the genetic analyses, on the basis of all and Biological Laboratories). available information including hospital notes. After being provided with a complete description of the Co-immunoprecipitation study, written informed consent to participate was Cultures astrocytes were homogenized in buffer obtained from all participants prior to examination. containing 50 mM Tris-HCl pH 7.8, 10% glycerol, The genetic association study was approved by the 1mM PMSF and a protease inhibitor cocktail (Sigma). Ethics Committee in Okayama and Tottori Universi- Lysates were centrifuged at 10 000 g, and the super- ties in Japan. natant containing 500 mg of proteins was precleared with mouse immunoglobulin with Pansorbin (EMD Sequencing and genotyping Biosciences). Cleared lysates were immunoprecipi- Genomic DNA was extracted from peripheral leuko- tated with an anti-SR monoclonal antibody (BD cytes using a standard phenol/CHCL3 procedures.44,45 Biosciences) overnight at 41C. The immunoprecipi- First, five SZ and five control subjects were randomly tates and input were analyzed in SDS-PAGE followed selected for direct sequencing of all known coding by immunoblotting with anti-SR and anti-PICK1 exons of PICK1 as well as 50 bp of intronic sequences antibodies (Santa Cruz biotechnology). Both the flanking each exon. By sequencing, we identified a anti-SR and anti-PICK1 antibodies recognize the total of four intronic single-nucleotide polymorph- single band at the expected size of the proteins in isms (SNPs) including two previously reported and the Western blotting (Figure 2b). two novel polymorphisms. Of these, we chose to genotype the two previously reported common SNPs Immunocytochemistry (rs713729 and rs2076369) likely to be informative for Immunofluorescent cell staining was carried out genetic association testing. These SNPs were selected as described.41 In brief, cells were fixed with 3.7% for genotyping because they crossed our threshold of paraformaldehyde in PBS, and permealized with 15% for the minor allele frequency in the Japanese 0.1% Triton X-100.
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