Target identification for CNS diseases by transcriptional profiling.
Target identification for CNS diseases by transcriptional profiling.
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DOI：
10.1038/npp.2008.172
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发表时间：
2009-01
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--
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神经精神和神经退行性疾病的基因表达变化以及基因对治疗药物的反应，为识别中枢神经系统（CNS）靶点提供了新的方法。本文综述了在人类死后大脑表达谱、动物模型和细胞培养研究中复制的基因和通路靶点。对分离的人类神经元的分析暗示了阿尔茨海默病和与正常衰老和轻度认知障碍相关的认知能力下降的目标。除了τ、淀粉样蛋白-β前体蛋白和淀粉样蛋白-β肽（Aβ）外，这些靶标还包括所有三种高亲和力神经营养因子受体和成纤维细胞生长因子（FGF）系统、突触标记物、谷氨酸受体（GluRs）和转运体、多巴胺受体（DA）受体，特别是D2亚型。帕金森病（PD）的基因候选者包括泛素-蛋白体系统、活性氧清除剂、脑源性神经营养因子（BDNF）、其受体TrkB、下游靶点早期生长反应1、Nurr-1，以及通过蛋白激酶C和RAS通路的信号传导。从中年到老年，大脑mRNA产生的变异性增加和减少表明，正常衰老过程中的认知障碍可能通过药物来解决，这些药物可以将抗氧化、DNA修复和突触功能（包括DA）恢复到年轻人的水平。精神分裂症患者的研究发现，GABA功能基因显著减少，包括谷氨酸脱羧酶、HINT1、谷氨酸转运和GluRs、BDNF和TrkB、众多14-3-3蛋白家族成员，以及中枢神经系统突触和代谢功能基因减少，尤其是糖酵解和ATP生成。许多这些代谢基因增加胰岛素和毒蕈碱激动剂，这两者都是治疗精神病。双相情感障碍的差异基因组信号相对较少，但包括14-3-3蛋白成员表达的缺陷，暗示这些伴侣蛋白及其支持的神经递质途径可能是药物靶点。重度抑郁症患者的大脑显示谷氨酸转运和代谢、神经营养信号（如FGF、BDNF和VGF）和MAP激酶途径的基因表达减少。暴露于电惊厥休克和抗抑郁治疗的动物大脑中这些通路的增加确定了神经营养和血管生成生长因子以及第二信使刺激作为治疗抑郁症的治疗方法。
Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer’s disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to τ, amyloid-β precursor protein, and amyloid-β peptides (Aβ), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson’s disease (PD) include the ubiquitin–proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
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影响因子：
11.2
作者：
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作者：
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