Blood transcriptomics of drug-naïve sporadic Parkinson’s disease patients

Abstract

BackgroundParkinson’s disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD.MethodsChanges in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set").ResultsGene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR. ConclusionsOur data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2058-3) contains supplementary material, which is available to authorized users.

A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number‐dependent manner

“…In a follow up of Calligaris et al (2015), we have taken advantage of CAGE to map TSSs in the peripheral blood of 20 drug‐naïve de novo PD patients and 20 age and sex matched healthy controls (HC). On average for each CAGE library, 7,158,414 tags were sequenced and 1,799,298 were uniquely mapped to the reference genome (Table S1).…”

Identification of potential diagnostic biomarkers for Parkinson's disease

“…As Calligaris et al [7] said, it is not surprising to find a very limited overlap in the identities of single genes between a study and those previously published, probably due to the complexity and heterogeneity of PD itself and differences in the cohort of patients and technical settings. Functional annotation of these DEGs in PD could contribute to exploring their precise roles in PD and further understanding the mechanism of PD at the molecular level.…”

Blood Transcriptomic Meta-analysis Identifies Dysregulation of Hemoglobin and Iron Metabolism in Parkinson’ Disease

“…Microarray studies have been valuable in identifying differential gene expression patterns and perturbed biological processes in blood of PD patients (Mutez et al, 2011; Potashkin et al, 2012; Alieva et al, 2014; Calligaris et al, 2015; Santiago and Potashkin, 2015; Santiago et al, 2016; Simchovitz et al, 2016). For example, high-throughput screening of blood RNA have provided molecular clues for some of the dysregulated pathways in PD, including the impairment of insulin signaling and glucose metabolism (Santiago and Potashkin, 2013a,b, 2015), aberrant RNA splicing (Potashkin et al, 2012; Soreq et al, 2012; Alieva et al, 2014), and inflammation (Simchovitz et al, 2016).…”

“…Since high-throughput screening of RNA from blood has been instrumental in elucidating important molecular pathways underlying neurodegeneration in PD patients (Scherzer et al, 2007; Mutez et al, 2011; Potashkin et al, 2012; Alieva et al, 2014; Calligaris et al, 2015; Santiago et al, 2016; Simchovitz et al, 2016), we hypothesized that analysis of the blood transcriptome could provide clues for the disrupted iron metabolism observed in PD patients. To this end, we performed a meta-analysis of four independent blood microarrays from PD patients and HCs.…”