Assocation between PICK1 gene and schizophrenia

D-丝氨酸是谷氨酸受体N-甲基-D-天冬氨酸亚型的内源性激动剂。遗传关联研究表明，精神分裂症(SZ)和双相情感障碍患者存在与D-丝氨酸代谢相关酶相关的基因。我们已经鉴定了与C-激酶相互作用的蛋白(PICK1)，它是D-丝氨酸合成酶丝氨酸消旋酶(SR)的蛋白相互作用蛋白。我们还观察到PICK1基因与SZ的关联，这种关联在SZ的无组织组中更为突出。在本研究中，我们探索了PICK1在细胞培养模型中对D-丝氨酸合成的作用以及将PICK1体内导入动物的脑中。此外，我们还探索了PICK1与神经心理学标记物的关系。首先，我们使用了几乎没有内源性SR的HEK293细胞。在野生型PICK1和/或SR的HEK293细胞中，我们观察到同时表达SR和PICK1的细胞与单独表达SR的细胞相比，D-丝氨酸/SR的比率增加。不能相互作用的SR突变体K27A/D28A取消了D-丝氨酸的增加。使用siRNA降低PICK1的表达也可以阻止D-丝氨酸产量的增加。接下来，我们研究了PICK1过表达对动物体内的影响。我们发现脑内转染区D-丝氨酸有增加的趋势，但并不显著。接下来，我们调查了SZ患者PICK1基因多态性与抗粉刺眼球运动的关系，但我们没有从受试者那里发现显著的结果。这些结果表明，PICK1可能通过与SR的相互作用而参与D-丝氨酸水平的升高。PICK1与深圳地区神经心理标记物之间的关系尚需进一步研究。

D-serine is an endogenous cagonist of the N-methy-D-aspartate subtype of glutamate receptor. Genetic association studies have implicated genes cording for enzymes associated with D-serine metabolism in schizophrenia (SZ) and bipolar disorder. We have identified and characterized protein interacting with C-kinase (PICK1) as a protein interacter of the D-serine synthesizing enzyme, serine racemase (SR). We also have observed an association of the PICK1 gene with SZ, which is more prominent in disorganized group of SZ. In this study, we explored the role of PICK1 for D-serine synthesis in cell culture models and in vivo transfection of PICK1 into the brain of animals. Furthermore, we also explored the association between PICK1 and neuropsychological markers.First, we use HEK293 cells, which have almost no endogenous SR. In HEK293 cells transfected with wildtype PICK1, SR, or both, we observed and increased ratio of D-serine to SR in cells expressing both SR and PICK1 compared with SR alone. The SR mutant K27A/D28A, which cannot interact with each other, abolished the increase in D-serine. Reducing PICK1 expression using siRNA to PICK1 also prevented the increase in D-serine production. Next, we examined the effect of overtransfection of PICK1 for animals in vivo. We found the tendency of increasing of D-serine in the transfected region of the brains, but it was not significant. Next, we investigated the association of PICK1 polymorphisms with anitisacade eye movements in SZ patients, but we could not find significant result from our subjects. These results suggest that PICK1 may be involved in increasing D-serine levels because of its interaction with SR. Further research is needed to explore the association between PICK1 and neuropsychological markers in SZ.