Dysbindin and Schizophrenia: it's dopamine and glutamate all over again.
Dysbindin and Schizophrenia: it's dopamine and glutamate all over again.
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DOI：
10.1016/j.biopsych.2010.10.028
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发表时间：
2011-01-01
影响因子：
10.6
通讯作者：
Weinberger, Daniel R.
中科院分区：
文献类型：
--
作者：
Papaleo, Francesco;Weinberger, Daniel R.
Dysbindin-1 由抗坏蛋白结合蛋白 1 基因 (DTNBP1) 编码，位于人和小鼠大脑的突触位点 (1)。 DTNBP1 的遗传变异会影响人类认知能力 (2-3)，并与精神分裂症风险相关 (4)。此外，据报道，精神分裂症患者的海马体和前额皮质 (PFC) 中 Dysbindin 基因和蛋白表达减少 (5-8)。后一项发现表明，与精神分裂症相关的分子表型是 Dysbindin 表达减少，可能是特定亚型的表达减少 (8)，但次要因素（例如药物、吸烟等）的作用以及任何 Dysbindin 转录物表达的改变是否是遗传风险的分子机制尚未确定。尽管存在这些不确定性，DTNBP1 表达减少的突变小鼠已成为 Dysbindin 蛋白减少的信息丰富的动物模型 (1, 5-8)。 虽然不同群体样本中 DTNBP1 与精神分裂症关联的统计证据各不相同，但 Dysbindin 在多巴胺和谷氨酸信号传导（精神病神经化学假说的核心两种神经递质）中的作用的分子证据相当一致。早期推测，dysbindin 在精神疾病中的作用分子机制与抗肌营养不良蛋白复合物有关，而该蛋白复合物的名字也由此而来，但目前的数据表明，dysbindin 作为溶酶体相关细胞器复合物 (BLOC-1) 生物发生中的伙伴，具有致病作用，这一推测已经黯然失色。 Dysbindin 参与涉及溶酶体和相关细胞器的细胞内蛋白质运输，对于突触稳态非常重要 (1, 9)。许多受体蛋白，包括 D2 受体和 NR2A 受体亚基，在内化后通过溶酶体介导的降解进行贩运，而 Dysbindin 已被证明会影响这些运输事件。失调结合蛋白被破坏的小鼠表现出多巴胺和谷氨酸信号传导这些特定成分的内部运输的选择性改变，而不是不通过溶酶体降解途径运输的其他受体成分（例如D1受体、NR2B成分[10-12]）。因此，dysbindin 的减少可能
Dysbindin-1 is encoded by the dystrobrevin-binding protein 1 gene (DTNBP1) and is located in synaptic sites throughout human and mouse brain (1). Genetic variations in DTNBP1 impact human cognitive abilities (2-3) and have been associated with risk for schizophrenia (4). Moreover, reduced dysbindin gene and protein expression have been reported in the hippocampus and prefrontal cortex (PFC) of schizophrenic patients (5-8). This latter finding suggests that a molecular phenotype associated with schizophrenia is reduced expression of dysbindin, perhaps of a specific isoform (8), but the role of secondary factors (eg drugs, smoking, etc.) and whether altered expression of any dysbindin transcript is the molecular mechanism of genetic risk have not been determined. These uncertainties notwithstanding, mutant mice with diminished DTNBP1 expression have become an informative animal model of reduced dysbindin protein (1, 5-8).While the statistical evidence for association of DTNBP1 and schizophrenia across diverse population samples is variable, the molecular evidence for a role of dysbindin in dopamine and glutamate signaling, two neurotransmitters at the core of neurochemical hypotheses of psychosis, is fairly consistent. Early speculation that the molecular mechanism of dysbindin's role in psychiatric illness had to do with the dystrophin protein complex, from which its name is derived, has been eclipsed by current data that implicate a pathogenic role of dysbindin as a partner in the biogenesis of lysosome-related organelles complex (BLOC-1). Dysbindin is involved in intracellular protein trafficking involving lysosomes and related organelles and it is important for synaptic homeostasis (1, 9). A number of receptor proteins, including D2 receptors and NR2A receptor subunits, are trafficked after internalization via lysosomal-mediated degradation and dysbindin has been shown to impact these trafficking events. Mice with disrupted dysbindin show selective alterations in internal trafficking of these specific components of dopamine and glutamate signaling, and not of other receptor components that are not trafficked through the lysosomal degradation pathway (eg D1 receptors, NR2B components [10-12]). Thus, dysbindin reductions may
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DOI：
10.1111/j.1601-183x.2009.00477.x
发表时间：
2009-06
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Cox MM;Tucker AM;Tang J;Talbot K;Richer DC;Yeh L;Arnold SE
通讯作者：
Arnold SE
DOI：
10.1038/npp.2009.90
发表时间：
2009-11
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.5
作者：
Weickert, Cynthia Shannon;Rothmond, Debora A.;Straub, Richard E.
通讯作者：
Straub, Richard E.
DOI：
10.1126/science.1179685
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Dickman DK;Davis GW
通讯作者：
Davis GW
影响因子：
3.5
作者：
Burdick, KE;Lencz, T;Malhotra, AK
通讯作者：
Malhotra, AK