Characterization of Genetic Mechanisms Contributing to Neuropsychiatric Disorder

这组研究人员确定了治疗精神分裂症的潜在治疗靶点，精神分裂症是一种影响约1%人口的衰弱性疾病。今年，神经生物学小组发表的数据描述了包括NRG1-ErbB4和PI3K酶在内的基因调控信号通路，所有这些都与精神分裂症的风险有关。Law等人（PNAS 2012）表明，药理学抑制p110可阻断安非他明在精神病小鼠模型中的行为作用，并逆转神经发育大鼠损伤模型中的精神分裂症样表型。p110抑制剂IC87114已被证明可以增加治疗小鼠大脑中另一个SZ风险基因AKT1的磷酸化，这与其他抗精神病药物样分子一致，并提示其作用机制。NRG1和ErbB4在神经发育和大脑可塑性中起着至关重要的作用。我们实验室和其他人之前的报告显示，NRG1基因突变与SZ风险相关，同样，ErbB4基因变异和结构微缺失也会影响患病风险。虽然NRG1和ErbB4缺失的小鼠表现出与其他SZ小鼠模型一致的行为模式，但人类死后SZ大脑也显示出NRG1和ErbB4表达的增加。这些基因的遗传变异影响人类大脑的结构和功能，但这些变化如何转化为疾病的机制尚不清楚。酶p110，也与SZ相关，可以与下游NRG1/ErbB4通路协同作用，并已在患者淋巴母细胞的研究中显示，酶水平升高。此外，在人SZ脑中，酶的表达增加。似乎NRG1和ErbB4可能是潜在的治疗靶点，但它们在细胞生理学中发挥作用，使它们不太可能成为靶向的候选者。作为更好的选择，在NRG1/ErbB4下游工作的P110可能被证明是可靶向的，并提供最佳的治疗潜力。

Researchers in this group identify a potential therapeutic target for the treatment of Schizophrenia, a debilitating disorder affecting approximately 1% of the population. This year the neurobiology group published data describing genetically regulated signaling pathways involving NRG1-ErbB4 and the PI3K enzyme, p110 all of which are associated with risk for schizophrenia. Law et al (PNAS 2012) show that pharmacological inhibition of p110 blocks behavioral effects of amphetamine in a mouse model of psychosis and reverses schizophrenia-like phenotypes in a neurodevelopmental rat lesion model. The p110 inhibitor, IC87114, has been shown to increase phosphorylation in another SZ risk gene, AKT1 in the brain of treated mice which is consistent with other antipsychotic-like molecules and suggests a mechanism of action. NRG1 and ErbB4 are known to be critical in neurodevelopment, brain plasticity. Previous reports from our lab and others have shown genetic mutations in NRG1 to be associated with risk for SZ, likewise genetic variation and structural microdeletions in ErbB4 also impacts risk for illness. While NRG1 and ErbB4 null mice show behavioral patterns consistent with other SZ mouse models, human postmortem SZ brains also show an increase in NRG1 and ErbB4 expression. Genetic variations in these genes affects human brain structure and function, but the mechanisms of how these changes turns into illness remain unknown. Enzyme p110, also related to SZ can act in concert with NRG1/ErbB4 pathways downstream and has been shown in studies of lymphoblasts from patients, where there is an increase in enzyme levels. Additionally, in human SZ brain there is an increase in enzyme expression. It appears NRG1 and ErbB4 could be potential therapeutic targets however they play roles in cell physiology making them unlikely candidates for targeting. The better choice, P110 which operates downstream of NRG1/ErbB4 may prove to be targetable and provide optimum therapeutic potential. Investigators in the Genetics and Bioinformatics Core Laboratory continues to identify novel SZ susceptibility genes and characterize their mechanism of action in both normal and diseased states. Our clinical, postmortem DNA and phenotype datasets are organized for efficient analysis using web-based family transmission and case-control methods. Genetic variants, genotypes, and statistical genetics results are shared with various phenotyping groups, including investigators in the Clinical Neuropsychology, and Neuroimaging Core Lab, investigators in the postmortem section and in our other research labs investigating risk genes and their biological impact. We select and prioritize functional and positional candidate genes based on the literature, in silico searches of interacting protein networks, and on new findings from ongoing collaborations. We also continue to identify and genotype variations in existing candidate genes and tests them for association with SZ, intermediate phenotypes from the Clinical Brain Disorders Branch, and expression phenotypes in human postmortem brain, cellular and animal model systems. This past year Zhang et al (Biol Psych 2011) performed association studies in 4 cohorts of European ancestry of a newly identified SNP (rs7597593) in ZNF804A, a previously described risk gene for SZ. We measured the SNP effect on mRNA expression using postmortem human brain. Since GWAS are generally used to identify common genetic variations in common diseases but less successful for identifying genetic variants in complex illnesses, like SZ, our study provides supportive evidence of an association of rs7597593 with risk for SZ that is also female-driven. A trend of sex-SNP interaction is seen in both, the combined 4 samples and US Gain cohort, the largest of all the samples. Risk association was seen at the level of clinical risk and in postmortem brain mRNA expression. Association and the sex-driven effect on risk were observed in 3 of the 4 cohorts (German, Scottish and US GAIN) individually as well as in the combined 4 case-control cohort sample, but statistical significance is not seen in the CBDB US cohort, whose limitation was more than likely sample size. To date, the function of the ZNF804A gene remains unknown. The results of the mRNA expression in postmortem brain and the sex-driven association of ZNF804A suggest a molecular mechanism between sex and rs7597593 on risk. Based on this study we are unable to ascribe causation to these genetic associations therefore additional studies of gene-gene interactions may help reveal the mechanism through which ZNF804A genetic variants affect risk for disease. Another group is our Transgenic Mouse and Cellular Models Lab, which translates human genetic mutations into genetic mouse models as an important strategy to study the pathogenesis of schizophrenia, identify potential drug targets, and tests new drugs for antipsychotic treatments. It is certainly impossible to capture the full spectrum of schizophrenia symptoms in animal models and as mentioned earlier in the Law, PNAS article rodent models have been successful in reproducing several schizophrenia-like behaviors and uncovering the roles of specific genes in dopamine and glutamine neurotransmission systems in mediating schizophrenia-like behaviors. Discoveries of susceptibility genes for schizophrenia and targeting cognitive dysfunction as a core feature of the disorder, provides the opportunity to develop and test newer genetic mouse models based on susceptibility. Although genetic mouse models based on genetic susceptibility are relatively new, we continue to study the roles of susceptibility genes in cognitive processing, neuronal function, and signal transduction in the brain during development. Examining candidate risk genes interactions with environmental factors, will most likely give us a better understanding of the molecular mechanisms of the pathophysiology of schizophrenia, reveal the molecular basis of normal cognitive function and human brain development, and guide us to novel antipsychotic therapies. Lastly, we look at how gene COMT relate to the biology and potential treatment of schizophrenia. The Transgenic Mouse and Cellular Models Lab explored the orientation and cellular distribution of Membrane-bound COMT. As been previously noted, COMT is a schizophrenia risk gene and a key enzyme for inactivating and metabolizing catechols, like dopamine, and plays a role in cognition, arousal, pain sensitivity and stress reactivity in humans and animal models. There are two forms of COMT, soluble (S) and membrane-bound (MB). In brain, MB is prevalent, but its neural cellular distribution and orientation are unclear. Chen et al (J Biol Chem 2011) show that MB is located in the neuron cell body, axons and dendrites in rat brain in addition MB orientation has the C-terminal catalytic domain in the extracellular space. This suggests MB has the capability to inactivate synaptic and extrasynaptic dopamine on the surface of pre-and postsynaptic neurons. We also show that the COMT inhibitor, tolcapone induces cell death via apoptosis and its cytotoxicity is dose dependent and correlated with COMT val/met genotype in human lymphoblasts. These data show that inhibitors impermeable to cell membrane in brain can be developed and for those who show drug sensitivity (COMT val/val genotype), use of low doses on a specific genetic background may ameliorate toxic effects of the drug.