Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia

Tadahiro Numakawa, Yuki Yagasaki, Tetsuya Ishimoto, Takeya Okada, Tatsuyo Suzuki, Nakao Iwata, Norio Ozaki, Takahisa Taguchi, Masahiko Tatsumi, Kunitoshi Kamijima, Richard E. Straub, Daniel R. Weinberger, Hiroshi Kunugi, Ryota Hashimoto

Research output: Contribution to journalArticle

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Abstract

Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia.

Original languageEnglish
Pages (from-to)2699-2708
Number of pages10
JournalHuman molecular genetics
Volume13
Issue number21
DOIs
Publication statusPublished - 01-11-2004

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Schizophrenia
Carrier Proteins
Genes
Glutamic Acid
Phosphatidylinositol 3-Kinase
Proteins
Synaptosomal-Associated Protein 25
Phosphorylation
dystrobrevin
Synapsins
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Serum
Haplotypes
Small Interfering RNA
Single Nucleotide Polymorphism
Potassium
Up-Regulation
Chromosomes
Neurons

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Numakawa, T., Yagasaki, Y., Ishimoto, T., Okada, T., Suzuki, T., Iwata, N., ... Hashimoto, R. (2004). Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Human molecular genetics, 13(21), 2699-2708. https://doi.org/10.1093/hmg/ddh280
Numakawa, Tadahiro ; Yagasaki, Yuki ; Ishimoto, Tetsuya ; Okada, Takeya ; Suzuki, Tatsuyo ; Iwata, Nakao ; Ozaki, Norio ; Taguchi, Takahisa ; Tatsumi, Masahiko ; Kamijima, Kunitoshi ; Straub, Richard E. ; Weinberger, Daniel R. ; Kunugi, Hiroshi ; Hashimoto, Ryota. / Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. In: Human molecular genetics. 2004 ; Vol. 13, No. 21. pp. 2699-2708.
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Numakawa, T, Yagasaki, Y, Ishimoto, T, Okada, T, Suzuki, T, Iwata, N, Ozaki, N, Taguchi, T, Tatsumi, M, Kamijima, K, Straub, RE, Weinberger, DR, Kunugi, H & Hashimoto, R 2004, 'Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia', Human molecular genetics, vol. 13, no. 21, pp. 2699-2708. https://doi.org/10.1093/hmg/ddh280

Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. / Numakawa, Tadahiro; Yagasaki, Yuki; Ishimoto, Tetsuya; Okada, Takeya; Suzuki, Tatsuyo; Iwata, Nakao; Ozaki, Norio; Taguchi, Takahisa; Tatsumi, Masahiko; Kamijima, Kunitoshi; Straub, Richard E.; Weinberger, Daniel R.; Kunugi, Hiroshi; Hashimoto, Ryota.

In: Human molecular genetics, Vol. 13, No. 21, 01.11.2004, p. 2699-2708.

Research output: Contribution to journalArticle

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AU - Numakawa, Tadahiro

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AU - Ishimoto, Tetsuya

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AU - Suzuki, Tatsuyo

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Taguchi, Takahisa

AU - Tatsumi, Masahiko

AU - Kamijima, Kunitoshi

AU - Straub, Richard E.

AU - Weinberger, Daniel R.

AU - Kunugi, Hiroshi

AU - Hashimoto, Ryota

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