Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia.
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.
Numakawa
Tadahiro
T
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashicho, Kodaira, Tokyo 187-8502, Japan.
Yagasaki
Yuki
Y
Ishimoto
Tetsuya
T
Okada
Takeya
T
Suzuki
Tatsuyo
T
Iwata
Nakao
N
Ozaki
Norio
N
Taguchi
Takahisa
T
Tatsumi
Masahiko
M
Kamijima
Kunitoshi
K
Straub
Richard E
RE
Weinberger
Daniel R
DR
Kunugi
Hiroshi
H
Hashimoto
Ryota
R
D000328:Adult; D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D002896:Chromosomes, Human, Pair 6; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012559:Schizophrenia / Q000235:genetics*; D016704:Synapsins / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25
D002352:Carrier Proteins; D002867:Chromones; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004791:Enzyme Inhibitors; D005819:Genetic Markers; D018698:Glutamic Acid; D008565:Membrane Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016704:Synapsins; D050825:Synaptosomal-Associated Protein 25; C432416:DTNBP1 protein, human; C574928:Dtnbp1 protein, rat; C494208:SNAP25 protein, human; C494210:Snap25 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C494920:Akt1 protein, rat