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Methylation profiling by array for Dementia with Lewy Bodies using brain tissue

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272947 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer’s disease (AD) and presents several overlapping pathological and clinical features with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets are anucleate cells containing cellular structures and molecules, such as microRNA (miRNA), the analysis of which provides biomarkers for several disorders. In this cross-sectional study, we profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 healthy controls using Next-Generation Sequencing (NGS) and found 22 differentially expressed miRNAs. These miRNAs were further validated with miRCURY LNA miRNA Custom PCR panels in three consecutive validation studies carried out from 2017-2019 with a total of 162 individuals including DLB (n=59), AD (n=28), and PD patients (n=24), and healthy controls (n=51). As a result, three different groups of miRNAs were identified as related to DLB, AD and PD, all in comparison with controls. Additionally, our results demonstrated a significant down-regulation of hsa-miR-26b-5p and hsa-miR-150-5p in DLB compared to PD; and a signature composed of seven miRNAs that had lower expression in DLB compared to AD. The predictive diagnostic value of this bio-signature for the differentiation of DLB from AD was assessed calculating the corresponding ROC curve, which yielded an area under the curve of 1.00. Predictive analyses using specialized software (miRTarbase, miRGate) were performed for the disease-specific miRNAs to identify target genes and corresponding pathways. Three disease-specific clusters of pathways and biological processes were identified as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, and protein metabolism and degradation were identified. In conclusion, we describe the identification of a novel, highly specific and sensitive platelet-associated miRNA-based bio-signature, which permits us to distinguish between DLB and AD.

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Methylation profiling by array for Dementia with Lewy Bodies using brain tissue

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