Dataset Information

Brain-derived extracellular vesicle proteomics reveals neuroprotection induced by the ARB candesartan in Parkinson’s disease patients

ABSTRACT: In models of Parkinson’s disease (PD), angiotensin-II type-1 receptor (AT1) blockers (ARBs) mitigated the vulnerability ofdopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility ofdopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PDincidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation ofblood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomicprofiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteinsinvolved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered byARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Extracellular Exosome, Blood

DISEASE(S): Parkinson's Disease

SUBMITTER: Susana Bravo

LAB HEAD: Ana Isabel Rodriguez-Perez

PROVIDER: PXD063198 | Pride | 2025-12-06

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	10_TMEM_neg_P5_after_treatment.wiff	Wiff
	10_TMEM_neg_P5_after_treatment.wiff.scan	Wiff
	11_TMEM_pos_P1_before_treatment.wiff	Wiff
	11_TMEM_pos_P1_before_treatment.wiff.scan	Wiff
	12_TMEM_pos_P1_after_treatment.wiff	Wiff

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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Brain-derived extracellular vesicle proteomics reveals neuroprotection induced by the ARB candesartan in Parkinson’s disease patients

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