Whole genome methylation analysis in blood and in specific cell blood subtypes in Parkinson’s disease.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122244 | GEO | 2023/11/01
REPOSITORIES: GEO
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Project description:Purpose: Parkinson’s disease (PD) is one of the most common neurological movement disorders. In the incidence and the clinical features of PD, significant gender differences have been observed. While males have a higher disease prevalence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms behind these disease-associated gender differences are still largely unknown, and a detailed understanding of the factors involved may open new avenues for pharmacological disease modification. Methods: To address this gap, we have conducted a meta-analysis of disease-associated molecular gender differences in brain transcriptomics data from PD case/control studies. We studied gender-dependent expression changes in individual genes and using systems level pathway and network analyses to identify coordinated gender-related molecular alterations. In each analysis, both gender-specific changes (significant alteration in only one gender) and gender-dimorphic changes (changes in both genders, but with opposite direction) were identified. Results: These analyses revealed significant disease-associated sex differences in immune response processes and mitochondrial pathways, and highlight regulatory factors, such as the transcription factor NR4A2, whose activity changes can explain ensuing alterations propagated through gene regulatory cascades. Overall, significant gender disparities were observed in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has previously been reported to harbor rare mutations in familial PD and its pharmacological activation conferred neuroprotective effects in toxin-induced models of Parkinsonism. NR4A2 may therefore be of interest as a candidate target for further preclinical studies on addressing gender-related pathological features of PD.
2023-01-19 | GSE168496 | GEO
Project description:Recent studies suggest that the activation of the innate immune system is an integral part of Parkinson’s disease (PD) pathology. Monocytes have a critical role as effectors and regulators of the innate immune system, and a recent expression quantitative trait locus (eQTL) study links monocytes to PD. Patients diagnosed with PD according to the National Institute of Neurological Disorders and Stroke diagnostic criteria for PD were included. We applied a standardized procedure with blood drawing from fasting participants. PD patients with Hoehn and Yahr > 2 and/or cognitive impairment were not recruited. Participants with a history of cancer, infectious diseases within the past three months, or taking anti-inflammatory drugs were excluded. Altogether, we analyzed the monocytic transcriptome profiles of 10 PD patients and 9 age- and sex-matched controls using mRNA sequencing.
2018-10-08 | GSE88888 | GEO
Project description:Parkinson´s disease (PD) feature a progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Additionally, numerous studies indicate an altered synaptic function during the course of PD. In order to characterize the proteome of synaptosomes isolated from the substantia nigra and to gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was conducted. Synaptosomes were isolated from substantia nigra tissue of control subjects free of pathology (N = 5) and individuals at advanced PD stages (N = 5) by density gradient centrifugation and further analyzed by mass spectrometry. 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome includes all proteins expressed within the synapses without regards to data analysis software, gender, age or disease. The CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, mitochondrial,, Neurolysin, and Methionine-tRNA ligase, mitochondrial (MARS2)) were underrepresented suggesting an alteration in mitochondrial translation in PD synaptosomes.
2021-06-07 | PXD022092 | Pride
Project description:Parkinson'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. We study changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls (“Discovery set”) by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. By applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays, gene expression profiling discriminates 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 were validated by RT-qPCR in an independent cohort of 12 patients and controls (“Validation set”). Our 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.
2015-10-29 | GSE72267 | GEO
Project description:Parkinson’s disease (PD) involves myriad genetic, behavioral, and environmental factors that make the identification of effective therapeutic targets challenging. We leverage a novel, validated AI approach to identify cell type- and brain region-specific epigenomic features in 6 brain regions from 35 individuals with varying genetic risk for PD as well as clinical and pathological controls (CTRL, n=15). We observed that astrocytes of substantia nigra (SUNI) are the major regional and cellular site of differentially accessible regions (DARs) between sporadic PD (SPOR_PD+, n=15) and GBA1 mutation-carriers with PD (GBA1_PD+, n=16); Seven of these SUNI DARs not only fully separated SPOR_PD+ from GBA1_PD+ cases but could also fully separate LRRK2 mutation carriers with PD from these other two forms of PD (n=3). Molecular estimation of PD progression, which correlated with the progression of neuropathologic stage, reveals that chromatin differences between SPOR_PD+ and GBA1_PD+ increase along the predicted disease progression, with broad cell type significant differences in epigenomic profiles at predicted later stages of the disease. Having APOE 4 (n=14 cases) was shown to affect various cell types mainly in the superior and middle temporal gyrus and substantial nigra. Using a multicellular co-accessibility network analysis, we identify neuron-specific epigenomic modules that correlate with the presence of at least one APOE 4 and the increase of PD pathological and clinical phenotypes. Our results suggest that APOE 4 could contribute to PD pathogenesis through chromatin change in neural cells related to synaptic and neuronal projection processes. This study expands our understanding of genetic risk effects in Parkinson's disease and provides a blueprint framework for investigating the cellular basis of genetic risk effects in disease.
2024-07-30 | GSE273511 | GEO
Project description:We have used microarrays to analyze gene expression in Parkinson’s disease (PD). We used four different brain regions, including two that are relatively affected in PD (striatum and cortex) and two that are relatively spared (cerebellum and medulla). We show that while differences between brain regions are strong, expression profile differences between PD and controls are much more modest and that genome-wide significant differences are restricted to the striatum and cerebral cortex. RNA (aRNA) was generated from 500ng of total RNA from the medulla (n=15 control brains, n=14 PD brains), striatum (n=15 control brains, n = 15 PD brains), frontal cortex (n=15 control brains, n = 11 PD brains) and cerebellum (n = 14 control brains, n=15 PD brains).
2011-07-21 | E-GEOD-28894 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is the most common movement disorder in the aging population, with an estimated prevalence of 1% of people above 60 years old. More recently, PD risk genes, have been found to be regulated by the small non-coding RNAs, (microRNAs or miRNAs), and, as such, may contribute to PD development through a direct regulation on the mitochondrial and immune pathways. Many of these are influenced by epigenetic mechanisms, among which ones mediated by, miRNAs, that regulate gene expression at a post transcriptional level by binding to their 3′ un-translated region (3′ UTR) of target messenger RNAs (mRNAs) inducing mRNA degradation and translational repression. This study aimed to identify and characterize miRNA to evaluate their possible deregulation in PD patients compared to CRTL. In addition, we investigated how specific miRNAs are able to target genes and, thus, to modulate their functions in PD patient. Small RNA expression profiling was performed by next-generation sequencing in PD patients and CTRL after filtered out low-quality reads and trimming the adaptors. The obtained high-quality reads were aligned against the human genome reference.
2023-09-01 | E-MTAB-12087 | biostudies-arrayexpress
Project description:We aim to explore the predominant mitochondrial dysfunctions in PD, with a focus on how altering the histone code contributes to PD pathogenesis. We employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure- and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. Our results reveal an exciting axis of ‘exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome’ for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.
2021-10-13 | GSE140524 | GEO
Project description:Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor NFYA, receptor tyrosine kinase DDR1, ubiquitin ligase RNF5, acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation (eQTM) sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57, among others. Functional epigenetic modules (FEM) were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support characterization of larger sample cohorts, with the goal of building a thorough, accurate and non-invasive molecular PD biomarker.
2021-03-11 | GSE165081 | GEO
Project description:The ability to use blood to predict the outcomes of Parkinson’s disease (PD), including disease progression and development of cognitive and motor complications, would be of enormous clinical value. We undertook deep RNA sequencing from the caudate and putamen of postmortem PD (n=35) and control (n=40) striatum, and compared molecular profiles with clinical features, and samples obtained from antemortem peripheral blood from an independent cohort. Cognitive and motor complications of PD were associated with molecular changes in the caudate (e.g., stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset PD were molecularly distinct, and disease duration was associated with changes in caudate (oligodendrocyte development) and putamen (cellular senescence) respectively. Molecular signatures in the postmortem PD brain were also evident in antemortem peripheral blood, and correlated with clinical disease features. Together, these findings identify molecular signatures in PD patients' brain and blood of potential pathophysiologic and prognostic importance
2023-07-05 | PXD042154 | Pride