Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential
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PROVIDER: PRJNA786798 | ENA |
REPOSITORIES: ENA
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Project description:Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. Herein, we measured genome-wide DNA methylation profiles of post-mortem brain tissue (Broadmann area 7) from 15 pathologically confirmed DLB brains and compared them with 16 cognitively normal controls using Illumina MethylationEPIC arrays. We identified 17 significantly differentially methylated CpGs (DMCs) and 17 differentially methylated regions (DMRs) between the groups. The DMCs are mainly located at the CpG islands, promoter and first exon regions. Genes associated with the DMCs are linked to “Parkinson disease” and “metabolic pathway”, as well as the diseases of “severe intellectual disability” and “mood disorders”. Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future.
2022-09-08 | GSE190348 | GEO
Project description:Synucleinopathies encompass Parkinsons disease (PD), dementia with Lewy bodies (DLB), and Parkinsons disease dementia (PDD) and are recognized for presenting a range of cognitive, neuropsychiatric, sleep-related, motor, and autonomic symptoms. DLB manifests with early-onset dementia when Lewy bodies develop in the brainstem and cerebral cortex. We profiled the DNA methylation using the post-mortem brain tissue from the parietal cortex, specifically Brodmann area 7 and compared them with age-, and sex-matched controls. Through the integration of multi-omics approaches, we anticipate the identification of notable alterations in these well-defined samples. Additionally, our objective is to study the biochemical perturbations in the brain tissue of those individuals who died with DLB. Differentially Methylated Cytosines (DMCs) and metabolites were identified, followed by pathway enrichment analysis. Correlations between methylation changes and metabolite levels were explored. Methylation profiling revealed 3,478 significant DMCs, predominantly hypermethylated, enriched in CpG islands and gene regions related to transcription start sites. Pathway analysis identified 612 significant pathways, with notable involvement in olfactory and synaptic functions. Metabolomics profiling identified 15 significantly differentially abundant metabolites. The top perturbed pathway was Phosphatidylethanolamine (PE) Biosynthesis. Further, key correlations were found between significant DMCs and metabolites, particularly in the Phosphatidylethanolamine Biosynthesis pathway involving genes PTDSS1 and PCYT2. Further, ignsificant sex-specific epigenetic and metabolomic changes were also observed. This comprehensive analysis of DNA methylation and metabolomics in DLB highlights significant biomarkers and pathways, offering insights into disease mechanisms and potential therapeutic targets.
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Project description:FAD and Lewy Body Dementia (LBD): Detection of S-Nitrosylation in Key Proteins in Human, Post-mortem Brain Samples
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Project description:Recent studies indicate a role of the adaptive immune system in Lewy body dementia (LBD). However, the mechanisms regulating T cell brain homing in LBD remain unknown. Here, we demonstrate interaction of T cells with Lewy bodies and with dopaminergic neurons in post-mortem LBD brains. Single cell RNA sequencing of cerebrospinal fluid (CSF) cells identified upregulated expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C Motif Chemokine Ligand 12 (CXCL12) were associated with neuroaxonal damage in LBD. Finally, we demonstrate clonal expansion and upregulated Interleukin 17A by CD4+ T cells stimulated with phosphorylated α-synuclein. Cumulatively, these results indicate CXCR4-CXCL12 signaling as a mechanistic target for inhibiting pathological T cell trafficking in LBD.
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Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.
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Project description:Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in post-mortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) identified upregulated expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C Motif Chemokine Ligand 12 (CXCL12) were associated with neuroaxonal damage in LBD. Furthermore, we observed clonal expansion and upregulated Interleukin 17A expression by CD4+ T cells stimulated with a phosphorylated α-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD.
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