Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation

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. Author Summary: 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.