Extracellular vesicle microRNA mediated transcriptional regulation may contribute to Dementia with Lewy Bodies molecular pathology

Işık, Fatma Büşra; Knight, Helen Miranda; Rajkumar, Anto P.

Abstract

Objective:

Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB-associated SEV miRNA and to analyse their functional implications.
Methods:

We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB (MIR26A1, MIR320C2, MIR320D2, MIR548BA, MIR556, and MIR4722) using miRBase and miRDB databases. We analysed functional implications of these targets using EnrichR gene set enrichment analysis and analysed their protein interactions using Reactome pathway analysis.
Results:

These SEV miRNA may regulate 4278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg false discovery rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation, and cytokine signalling pathways.
Conclusion:

Our findings provide in-silico evidence that potential targets of DLB-associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could lead to novel therapeutic avenues for DLB.Dementia with Lewy Bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB associated SEV miRNA and to analyse their functional implications. We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB ( , , , , , and ) using and databases. We analysed functional implications of these targets using gene set enrichment analysis, and analysed their protein interactions using pathway analysis. These SEV miRNA may regulate 4,278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg False Discovery Rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation and cytokine signalling pathways. Our findings provide evidence that potential targets of DLB associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could led to novel therapeutic avenues for DLB.

Citation

Işık, F. B., Knight, H. M., & Rajkumar, A. P. (2024). Extracellular vesicle microRNA mediated transcriptional regulation may contribute to Dementia with Lewy Bodies molecular pathology. Acta Neuropsychiatrica, 36(1), 29-38. https://doi.org/10.1017/neu.2023.27

• Journal Article Type: Article
• Acceptance Date: May 24, 2023
• Online Publication Date: Jun 21, 2023
• Publication Date: 2024-02
• Deposit Date: Nov 14, 2023
• Publicly Available Date: Nov 17, 2023
• Journal: Acta Neuropsychiatrica
• Print ISSN: 0924-2708
• Electronic ISSN: 1601-5215
• Publisher: Cambridge University Press
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Issue: 1
• Pages: 29-38
• DOI: https://doi.org/10.1017/neu.2023.27
• Keywords: Lewy Body Disease, Extracellular vesicles, Gene Ontology, MicroRNAs, Alpha-Synuclein
• Public URL: https://nottingham-repository.worktribe.com/output/22713949
• Publisher URL: https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/extracellular-vesicle-micrornamediated-transcriptional-regulation-may-contribute-to-dementia-with-lewy-bodies-molecular-pathology/CD37D17D81C179F6264B67BB116381C3