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.
Highlights
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms
Study design Here we aim to identify gene expression patterns in peripheral blood of de novo and drug-naïve PD patients by comparing 40 sporadic PD versus 20 healthy control (HC) (“Discovery set”)
While we confirmed alterations previously found in PD blood and post-mortem brains such as neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, we have unveiled changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation
Summary
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. PD presents a variety of neuropsychiatric, autonomic, sensory, and sleep disorders that may precede the expression of motor disturbances by more than a decade suggesting that PD is a systemic disease [2] In this context, a long and intriguing list of alterations of blood physiology has been described in PD patients [3]. Gene expression analysis has identified changes in blood correlated to neurodegeneration in PD [5,6,7,8,9,10,11] Some of these works suffer the variability derived from enrolling patients in different stages of the disease and from the unknown effects of pharmacological treatments
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