Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia
Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia
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DOI：
10.1093/hmg/ddh280
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Hashimoto, R
中科院分区：
文献类型：
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作者：
Numakawa, T;Yagasaki, Y;Hashimoto, R
dysbindin（DTNBP 1：dystrobrevin-binding protein 1）的遗传变异最近被证明与精神分裂症有关。dysbindin基因位于染色体6p22.3，这是精神分裂症连锁研究中最有希望的易感位点之一。我们试图在670名精神分裂症患者和588名对照的日本样本中复制这种关联。我们发现一个名义上显着的关联与精神分裂症的四个单核苷酸多态性和更强的证据，在多标记单倍型分析（P=0.00028）。然后，我们探讨了dysbindin蛋白在原代皮层神经元培养中的功能。dysbindin的过度表达诱导两个突触前蛋白，SNAP 25和synapsin I的表达，并增加细胞外基础谷氨酸水平和释放谷氨酸诱发高钾。相反地，通过小干扰RNA（siRNA）敲低内源性dysbindin蛋白导致突触前蛋白表达和谷氨酸释放的减少，表明dysbindin可能通过上调突触前机制中的分子来影响胞吐谷氨酸释放。dysbindin的过度表达增加Akt蛋白的磷酸化，并保护皮质神经元免受血清剥夺引起的神经元死亡，这些作用被磷脂酰肌醇3-激酶（PI 3-kinase）抑制剂LY 294002阻断。siRNA介导的dysbindin蛋白的沉默减少了Akt磷酸化并促进了由血清剥夺诱导的神经元死亡，表明dysbindin通过PI 3-激酶-Akt信号传导促进神经元活力。与dysbindin这些功能受损相关的遗传变异可能在精神分裂症的发病机制中发挥重要作用。
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.