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,...

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Vydáno v:	PLoS genetics Ročník 8; číslo 6; s. e1002794
Hlavní autoři:	Dumitriu, Alexandra, Latourelle, Jeanne C., Hadzi, Tiffany C., Pankratz, Nathan, Garza, Dan, Miller, John P., Vance, Jeffery M., Foroud, Tatiana, Beach, Thomas G., Myers, Richard H.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.06.2012 Public Library of Science (PLoS)
Témata:	Age of Onset Aged, 80 and over Binding Sites Biology Development and progression Forkhead Box Protein O1 Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gene expression Gene Expression Regulation Gene Regulatory Networks - genetics Genetic aspects Genetic transcription Genetics Genome-Wide Association Study Health aspects Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Lewy Bodies - genetics Lewy Bodies - metabolism Male Medical research Medicine Oligonucleotide Array Sequence Analysis Oxidoreductases Acting on CH-NH Group Donors - genetics Oxidoreductases Acting on CH-NH Group Donors - metabolism Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson's disease Pathology Physiological aspects Polyamine Oxidase Polymorphism, Single Nucleotide Prefrontal cortex Prefrontal Cortex - metabolism Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism United States
ISSN:	1553-7404, 1553-7390, 1553-7404
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: AD JCL DG RHM. Performed the experiments: DG JPM. Analyzed the data: AD JCL NP. Contributed reagents/materials/analysis tools: TCH JMV TF TGB RHM. Wrote the paper: AD JCL RHM.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1002794