Through a meta-analysis of four microarray studies, a pair of researchers from the Rosalind Franklin University of Medicine and Science identified two mRNAs that appear to act as biomarkers for Parkinson's disease.

The expression level of HNF4A and PTBP1 mRNAs differed in the blood of Parkinson's disease patients as compared to controls, the researchers reported today in the Proceedings of the National Academy of Sciences. The level of HNF4A mRNA correlated with worsening disease stage, suggesting that it could gauge disease severity. Both of these genes have been associated previously with diabetes, tightening the link between the two diseases.

"Biomarker discovery and validation is a crucial step toward the improvement of clinical management of PD," Franklin's Jose Santiago and Judith Potashkin wrote in their paper. "Specifically, biomarkers that are useful in tracking the clinical course of PD are essential to the development of effective therapeutics."

To search for a molecular signature for Parkinson's disease, the duo determined that a transcriptomic and network-based meta-analysis could uncover important regulators and biomarkers of disease.

Santiago and Potashkin pulled together data from four different microarray-based studies of Parkinson's disease, totaling 83 patients and 46 healthy controls. Using the Integrative Meta-Analysis of Expression Data interface, the duo uncovered 2,781 genes that were consistently differentially expressed across the four studies. Of these, 680 were up-regulated, while 2,101 were down-regulated.

Based on a gene pathway analysis, the researchers noted that many of these differentially expressed genes were involved in pathways and processes related to protein processing in the endoplasmic reticulum, T-cell receptor signaling, type 2 diabetes, and more.

Additionally, network analysis using NetworkAnalyst found that HNF4A was a key hub gene, while PTBP1 was the most significantly down-regulated gene among Parkinson's disease patients.

HNF4A is a master metabolic regulatory factor that's involved in activating gluconeogenesis in the liver and has been linked to diabetes, inflammation, and lipid metabolism. PTBP1, meanwhile, is thought to promote the stabilization and translation of insulin mRNAs in pancreatic β-cells.

Based on their network analysis, Santiago and Potashkin measured the levels of HNF4A and PTBP1 mRNA in the blood of 101 Parkinson's disease patients and 91 healthy controls. A qPCR-based assay revealed that HNF4A and PTBP1 were significantly up-regulated or down-regulated, respectively, in patients as compared to controls.

Indeed, they found that the expression levels of these two genes could classify patients with 90 percent sensitivity and 80 percent specificity, and that the HNF4A and PTBP1 mRNA levels were independent of other variables such as age and sex.

They also found a negative correlation between HNF4A mRNA levels and PTBP1 mRNA levels, and a correlation between HNF4A mRNA levels and disease stage, suggesting that HNF4A mRNA levels could be useful in identifying Parkinson's disease patients at early stages of the disease as well as in monitoring disease severity.

The levels of the two putative biomarkers also varied over time. In a cohort of 50 Parkinson's disease patients and 46 healthy controls samples, the researchers found that HNF4A mRNA levels decreased over time in Parkinson's disease patients, as compared to controls, while PTBP1 mRNA levels increased as compared to controls in the three-year follow-up period.

"The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD," Santiago and Potashkin said.

Monday February 02, 2015, GenomeWeb