Looking beyond the brain to improve the pathogenic understanding of Parkinson’s disease: implications of whole transcriptome profiling of Patients’ skin

Abstract

BackgroundParkinson’s Disease is a progressive neurodegenerative disease, characterized by symptoms of motor impairment, resulting from the loss of dopaminergic neurons in the midbrain, however non-neuronal symptoms are also common. Although great advances have been made in the pathogenic understanding of Parkinson’s Disease in the nervous system, little is known about the molecular alterations occurring in other non-neuronal organ systems. In addition, a higher rate of melanoma and non-melanoma skin cancer has been observed in the Parkinson’s Disease population, indicating crosstalk between these diseases.MethodsTo understand the molecular pathogenesis and gene expression alterations of Parkinson’s Disease in peripheral tissues, and in order to explore the possible link between skin cancer and neurodegeneration, whole transcriptomic profiling of patients’ skin was performed. Skin biopsies from 12 patients and matched controls were collected, and processed with high-throughput RNA-sequencing analysis.ResultsThis analysis resulted in a large collection of over 1000 differentially expressed genes, among which clear biological and functional networks could be distinguished. The central functional processes altered in patients skin can be grouped into six broad categories: impaired cellular metabolism and mitochondrial dysfunction, defective protein metabolism, disturbed skin homeostasis, dysfunctional nuclear processes, altered signalling and tumour pathways, as well as disordered immune regulation.ConclusionsThese results demonstrate that the molecular alterations leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues, thereby indicating the presence of “skin-brain” crosstalk in Parkinson’s Disease. In addition, the extensive homeostatic imbalance and basal stress can lead to increased susceptibility to external and internal mutagenic hazards in these patients, and thus provide a possible molecular link for the crosstalk between skin cancer and Parkinson’s Disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0784-z) contains supplementary material, which is available to authorized users.

Low resilience to stress is associated with candidate gene expression alterations in the dopaminergic signalling pathway

“…Although there are clear similarities in gene expression profiles between whole blood and the brain, variations in expression levels between these two tissue types exist . A series of studies have investigated the mRNA levels of dopaminergic signalling pathway candidate genes, specifically phenylalanine hydroxylase ( PAH ), pterin‐4a‐carbinolamine dehydratase ( PCD ) TH , DDC , DBH , phenylethanolamine N‐methyltransferase ( PNMT ), glutathione peroxidase 1 ( GPX1 ) MAOA , monoamine oxidase B, COMT , DRD1–DRD5 , solute carrier family 18 member A1 ( VMAT1 ), solute carrier family 18 member A2 ( VMAT2 ) . For this purpose, peripheral expression of dopamine‐related genes may be used as a biomarker of the severity of psychiatric disorders, such as addiction to stimulant drugs, and the cognitive response to dopamine agonist drugs.…”

“…30 A series of studies have investigated the mRNA levels of dopaminergic signalling pathway candidate genes, specifically phenylalanine hydroxylase (PAH), pterin-4a-carbinolamine dehydratase (PCD) TH, DDC, DBH, phenylethanolamine Nmethyltransferase (PNMT), glutathione peroxidase 1 (GPX1) MAOA, monoamine oxidase B, COMT, DRD1-DRD5, solute carrier family 18 member A1 (VMAT1), solute carrier family 18 member A2 (VMAT2). 31,32 For this purpose, peripheral expression of dopaminerelated genes may be used as a biomarker of the severity of psychiatric disorders, such as addiction to stimulant drugs, and the cognitive response to dopamine agonist drugs. The expression of marker genes in dopamine and serotonin pathways is detectable not only in the brain but also in peripheral blood, where these neurotransmitters play a pivotal role in mediating communication between the nervous and immune systems.…”

A review of genome‐wide transcriptomics studies in Parkinson's disease

“…A small number of studies carried out genome‐wide transcriptomics in biological samples other than blood or brain tissue. Three studies were performed on CSF (Burgos et al., ; Gui et al., ; Hossein‐Nezhad et al., ) and one used skin as a RNA source (Table ; Table S1; Planken et al., ).…”

“…For the CSF studies, two performed small RNA sequencing to investigate miRNA expression (Burgos et al., ; Gui et al., ) and one used RNA‐Seq (Hossein‐Nezhad et al., ). The only study performed on skin used RNA‐Seq (Table ; Table S1; Planken et al., ).…”

Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a breast cancer susceptibility locus at 12q15

“…Many studies have shown that disease tissues exhibit molecular heterogeneity (1)(2)(3). In particular, characterization of tumor profiles has been used extensively to subtype cancers (4)(5)(6), with breast cancer being a quintessential example (7).…”