Abstract
DTNBP1 has been recognized as a schizophrenia susceptible gene, and its protein product, dysbindin-1, is down-regulated in the brains of schizophrenic patients. However, little is known about the physiological role of dysbindin-1 in the central nervous system. We hypothesized that disruption of dysbindin-1 with unidentified proteins could contribute to pathogenesis and the symptoms of schizophrenia. GST pull-down from human neuroblastoma lysates showed an association of dysbindin-1 with the DNA-dependent protein kinase (DNA-PK) complex. The DNA-PK complex interacts only with splice isoforms A and B, but not with C. We found that isoforms A and B localized in nucleus, where the kinase complex exist, whereas the isoform C was found exclusively in cytosol. Furthermore, results of phosphorylation assay suggest that the DNA-PK complex phosphorylated dysbindin-1 isoforms A and B in cells. These observations suggest that DNA-PK regulates the dysbindin-1 isoforms A and B by phosphorylation in nucleus. Isoform C does not contain exons from 1 to 6. Since schizophrenia-related single nucleotide polymorphisms (SNPs) occur in these introns between exon 1 and exon 6, we suggest that these SNPs might affect splicing of DTNBP1, which leads to impairment of the functional interaction between dysbindin-1 and DNA-PK in schizophrenic patients.
Highlights
Dystrobrevin binding protein 1 (DTNBP1, dysbindin-1) consists of approximately 350 amino acids and was originally identified by Benson et al [1] as a dystrobrevin-binding protein in a yeast twohybrid screen
Five proteins, which were,80, 115, 120, 157, and 470 kDa, respectively, were co-purified from SH-SY5Y cell lysates with GST-dysbindin-1, but not with GST alone (Fig. 1B). These protein bands were excised from the gel, subjected to in-gel trypsin digestion, and analyzed by mass assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS). They were reproducibly identified as ATP-dependent DNA helicase 2 (Ku80), poly (ADP-ribose) polymerase family, member 1 (PARP1), adaptor-related protein complex 3, beta 2 subunit (AP3b2), leucine-rich PPR-motif containing protein (LRPPRC), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) by peptide mass fingerprinting (PMF)
Previous studies have demonstrated an interaction of AP3b2 with dysbindin-1, which we identified in screenings of both mouse brain and SH-SY5Y cells
Summary
Dystrobrevin binding protein 1 (DTNBP1, dysbindin-1) consists of approximately 350 amino acids and was originally identified by Benson et al [1] as a dystrobrevin-binding protein in a yeast twohybrid screen. Dysbindin-1 attracted interest in 2002 when variations in the gene encoding it at chromosomal locus 6p22.3 were reported to be associated with schizophrenia [2], suggesting a susceptibility locus for schizophrenia. Genetic variations in the dysbindin-1 gene might be a major risk factor for schizophrenia. Previous reports have shown that diverse high-risk single nucleotide polymorphisms (SNPs) and haplotypes could influence dysbindin-1 mRNA expression [17,18,19]. Dysbindin-1 is involved in glutamatergic [9,21] and dopaminergic neurotransmission [22,23,24]. This suggests that the physiological function of dysbindin-1 might be impaired in schizophrenia patients. The functions of dysbindin-1 in the central nervous system (CNS) remain unclear
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