Multiregional Gene Expression Profiling Identifies MRPS6 as a Possible Candidate Gene for Parkinson's Disease

Abstract

Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling

“…These included members of the protocadherin family and genes whose products bind to cell adhesion related protein complexes [61], [62]. While these observations do not negate other genes that confer vulnerability to addiction, they do agree with the observations shown here for hippocampal gene expression in cocaine abusers.…”

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

“…Details regarding the participants, biological samples, and microarray experiments have been recently reported [19]. For this study, we limited our data analyses to the substantia nigra and the striatum (putamen and caudate nuclei), since these are the brain regions contributing most significantly to the nigrostriatal dopamine deficiency that is characteristic of PD and since we defined our three PD outcomes according to the corresponding motor phenotype.…”

“…Our analyses of an available gene-expression profiling dataset revealed that axon-guidance pathway genes were differentially expressed in the brains of PD cases as compared to controls, including several genes that were predictive of PD in the models constructed from the primary whole-genome association dataset (convergence of findings) [11,19]. Not all genes included in the models constructed from the primary whole-genome association dataset were abnormally expressed in the gene-expression profiling dataset, and not all axon-guidance pathway genes that were abnormally expressed in the gene-expression profiling dataset were predictive of PD outcomes in that whole-genome association dataset (unpublished data).…”

Protein Aggregation in a Mutant Deficient in YajL, the Bacterial Homolog of the Parkinsonism-associated Protein DJ-1

“…Ribosomal proteins, however, are overrepresented in the array of proteins associated with soluble ␣-synuclein and/or with DJ-1 in cells treated with the parkinsonian toxicant rotenone (37), which suggests that ribosomal protein defects might be involved in parkinsonism. Moreover, the mitochondrial ribosomal protein S6 has been identified as a possible candidate gene in Parkinson disease (38).…”