Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation.
Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation.
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DOI：
10.1371/journal.pgen.1002794
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发表时间：
2012-06
期刊：
影响因子：
4.5
通讯作者：
Myers RH
中科院分区：
文献类型：
--
作者：
Dumitriu A;Latourelle JC;Hadzi TC;Pankratz N;Garza D;Miller JP;Vance JM;Foroud T;Beach TG;Myers RH
帕金森病（PD）是一种复杂的神经退行性疾病，其遗传机制尚不清楚。虽然PD中多巴胺能神经元的变性主要发生在黑质（substantia nigra pars rectata，SN）区域，但包括前额叶皮质在内的其他脑区发育路易体（Lewy bodies），这是PD的神经病理学标志。我们使用44 K单色Agilent 60-mer全人类基因组微阵列生成并分析了27个PD和26个对照样本的前额叶皮层Brodmann区9（BA 9）的表达数据。所有样本均为男性，无显著阿尔茨海默病病理学，并具有广泛的病理学注释。在39，122个分析的表达探针中，507个在PD和对照样品之间不同，错误发现率（FDR）为5%。在PD中表达显著增加的基因之一是叉头框O 1（FOXO 1）转录因子。值得注意的是，携带FoxO 1结合位点的基因在FDR显著基因组中显著富集（189个探针覆盖177个基因），表明FoxO 1在所观察到的表达变化上游的作用。从最近的PD全基因组关联研究（GWAS）的荟萃分析中选择的单核苷酸多态性（SNP）在53个微阵列大脑中的50个中成功地进行了基因分型，允许对与PD影响相关的52个SNP进行靶向表达SNP（eSNP）分析，在全基因组意义上，189个探针来自FoxO 1调节基因。在细胞周期蛋白G相关激酶（GAK）基因中的SNP和精胺氧化酶（SMOX）基因中的探针之间观察到显著关联。在对6个可用GWAS的荟萃分析中对FOXO 1区域的进一步检查显示，两个SNP与PD发作时的年龄显著相关。这些结果暗示FOXO 1作为PD相关基因，并保证其转录调控机制的进一步功能分析。帕金森病（PD）是一种神经退行性疾病，其损害受影响个体的运动和认知能力。虽然已经认识到特定基因参与疾病过程，但尚未了解潜在的遗传机制。PD的一种常见研究方法是将PD病例的脑组织中的基因表达水平与神经健康对照组的基因表达水平进行比较。我们在一组27个PD和26个对照样本的前额叶皮层组织中进行了这样的表达分析。叉头框O 1（FOXO 1）是489个差异表达基因之一，参与转录调控。值得注意的是，在我们的研究中鉴定的差异表达基因的集合富集了由FoxO 1蛋白调控的基因。对FOXO 1区域中被称为单核苷酸多态性（SNP）的DNA序列变异以及整个基因组中PD相关SNP的分析表明，该基因与1）PD发病年龄和2）精胺氧化酶（SMOX）基因之间存在功能联系。这些发现暗示FOXO 1参与PD发病机制。
Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR–significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression–SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD–relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms. Parkinson disease (PD) is a neurodegenerative disease, which impairs the motor and cognitive abilities of affected individuals. Although the involvement of specific genes in the disease process has been recognized, the underlying genetic mechanisms are not yet understood. One common investigation approach for PD has been the comparison of gene expression levels in brain tissue from PD cases with those from neurologically healthy controls. We performed such an expression analysis in prefrontal cortex tissue from a set of 27 PD and 26 control samples. One of the 489 differentially expressed genes, forkhead box O1 (FOXO1), is involved in transcriptional regulation. Notably, the set of differentially expressed genes identified in our study was enriched for genes regulated by the FoxO1 protein. Analyses of DNA sequence variants known as single-nucleotide polymorphisms (SNPs) in the FOXO1 region, as well as of PD–relevant SNPs across the genome, suggest functional connections between this gene and 1) the age at onset in PD, and 2) the spermine oxidase (SMOX) gene. These findings implicate the involvement of FOXO1 in PD pathogenesis.
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