MicroRNAs from extracellular vesicles as a signature for Parkinson's disease

Gomes, Lucas Caldi; Roser, Anna-Elisa; Jain, Gaurav; Centeno, Tonatiuh Peña; Maass, Fabian; Schilde, Lukas; May, Caroline; Schneider, Anja; Bähr, Mathias; Marcus, Katrin; Fischer, André; Lingor, Paul

doi:10.1002/ctm2.357

Cited by 15 publications

(6 citation statements)

References 11 publications

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“…In the clustering analysis of the PD cohort, the transcriptomics analysis showed the highest homogeneity among subjects, whereas small RNAs and proteins were more heterogeneous (Figure 1I–K), arguing for changes induced by post‐translational modifications. The number of post‐mortem samples in this project was too small to identify distinct patient subgroups; however, we recently analysed the diversity of miRNA in cerebrospinal fluid (CSF) of patients with PD, which revealed distinct molecular subgroups that were independent of the clinical phenotype 38 . A future analysis of a larger number of samples could be more suited to identify distinct subgroups and will represent an important prerequisite for the development of personalized therapeutic approaches based on the molecular phenotype in PD.…”

Section: Discussionmentioning

confidence: 99%

Multi‐omic landscaping of human midbrains identifies disease‐relevant molecular targets and pathways in advanced‐stage Parkinson's disease

Gomes

Galhoz

Jain

et al. 2022

Clinical & Translational Med

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Background Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease‐mediated alterations, we investigated the molecular landscape of PD in human post‐mortem midbrains, a region that is highly affected during the disease process. Methods Tissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi‐omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole‐time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies. Results Our analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real‐time polymerase chain reaction/western blotting) several PD‐deregulated molecular candidates, including miR‐539‐3p, miR‐376a‐5p, miR‐218‐5p and miR‐369‐3p, the valid miRNA‐mRNA interacting pairs miR‐218‐5p/RAB6C and miR‐369‐3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi‐omic analyses allowed validating disease‐mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function. Conclusions This comprehensive assessment of PD‐affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.

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Section: Discussionmentioning

confidence: 99%

Multi‐omic landscaping of human midbrains identifies disease‐relevant molecular targets and pathways in advanced‐stage Parkinson's disease

Gomes

Galhoz

Jain

et al. 2022

Clinical & Translational Med

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“…Currently, several biomarkers for PD diagnosis were available. Caldi et al identified a miRNA signature in PD cerebrospinal fluid ( Caldi Gomes et al, 2021 ). Shao et al identified a metabolite panel in PD plasma samples ( Shao et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of DNA methylation and gene expression data for the diagnosis and underlying mechanism of Parkinson’s disease

Ding

Liang²,

Guo³

et al. 2022

Front. Aging Neurosci.

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BackgroundParkinson’s disease (PD) is the second most common progressive neurodegenerative disorder and the leading cause of disability in the daily activities. In the management of PD, accurate and specific biomarkers in blood for the early diagnosis of PD are urgently needed. DNA methylation is one of the main epigenetic mechanisms and associated with the gene expression and disease initiation of PD. We aimed to construct a methylation signature for the diagnosis of PD patients, and explore the potential value of DNA methylation in therapeutic options.Materials and methodsWhole blood DNA methylation and gene expression data of PD patients as well as healthy controls were extracted from Gene Expression Omnibus database. Next, differentially expressed genes (DEGs) and differentially methylated genes (DMGs) between PD patients and healthy controls were identified. Least absolute shrinkage and selection operator cox regression analysis was carried out to construct a diagnostic signature based on the overlapped genes. And, the receiver operating characteristic (ROC) curves were drawn and the area under the curve (AUC) was used to assess the diagnostic performance of the signature in both the training and testing datasets. Finally, gene ontology and gene set enrichment analysis were subsequently carried out to explore the underlying mechanisms.ResultsWe obtained a total of 9,596 DMGs, 1,058 DEGs, and 237 overlapped genes in the whole blood between PD patients and healthy controls. Eight methylation-driven genes (HIST1H4L, CDC42EP3, KIT, GNLY, SLC22A1, GCM1, INO80B, and ARHGAP26) were identified to construct the gene expression signature. The AUCs in predicting PD patients were 0.84 and 0.76 in training dataset and testing dataset, respectively. Additionally, eight methylation-altered CpGs were also identified to construct the CpGs signature which showed a similarly robust diagnostic capability, with AUCs of 0.8 and 0.73 in training dataset and testing dataset, respectively.ConclusionWe conducted an integrated analysis of the gene expression and DNA methylation data, and constructed a methylation-driven genes signature and a methylation-altered CpGs signature to distinguish the patients with PD from healthy controls. Both of them had a robust prediction power and provide a new insight into personalized diagnostic and therapeutic strategies for PD.

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“…The analysis of miRNAs as biomarkers for PD has been performed in several biofluids, including CSF, plasma, serum, and brain tissue ( Cao et al, 2017 ; Dos Santos et al, 2018 ; He et al, 2021 ; Valencia et al, 2022 ). In a study analyzing EVs derived from CSF of PD and age‐correlated controls, using next-generation small-RNA sequencing, Caldi Gomes et al (2021 ) presented the complete and quantitative microRNAome. They detected a total of 688 miRNAs, with 22 miRNAs showing differential expression in PD subjects compared with controls, the majority of which were upregulated in PD.…”

Section: Brain Cell–derived Extracellular Vesicles’ Usefulness In Cha...mentioning

confidence: 99%

“…They detected a total of 688 miRNAs, with 22 miRNAs showing differential expression in PD subjects compared with controls, the majority of which were upregulated in PD. Using a machine-learning approach, they suggested an iterative signature involving miR-126-5p, miR‐99a‐5p, and miR‐501‐3p, which could differentiate PD and control samples ( Caldi Gomes et al, 2021 ). Another study analyzing miRNA expression in CSF exosomes using a TaqMan low-density array for human miRNA panel and further validation of differentially expressed miRNAs using quantitative PCR (qPCR) revealed reduced expression of 11 miRNAs and increased expression of 16 miRNAs in PD patients compared with healthy controls.…”

Section: Brain Cell–derived Extracellular Vesicles’ Usefulness In Cha...mentioning

confidence: 99%

Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust

Kumar,

Nader,

Deep

2023

Pharmacol Rev

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Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases and disorders. The feasibility of enriching specific subpopulations of EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight from various tissues and organs, including the brain. Over the past decade, EVs in bodily fluids have been extensively studied for biomarkers associated with various neurological disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, major depressive disorders, substance use disorders, human immunodeficiency virus–associated neurocognitive disorder, and cancer/treatment-induced neurodegeneration. These studies have focused on the isolation and cargo characterization of either total EVs or brain cells, such as neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, and endothelial-derived EVs from biofluids to achieve early diagnosis and molecular characterization and to predict the treatment and intervention outcomes. The findings of these studies have demonstrated that EVs could serve as a repetitive and less invasive source of valuable molecular information for these neurological disorders, supplementing existing costly neuroimaging techniques and relatively invasive measures, like lumbar puncture. However, the initial excitement surrounding blood-based biomarkers for brain-related diseases has been tempered by challenges, such as lack of central nervous system specificity in EV markers, lengthy protocols, and the absence of standardized procedures for biological sample collection, EV isolation, and characterization. Nevertheless, with rapid advancements in the EV field, supported by improved isolation methods and sensitive assays for cargo characterization, brain cell–derived EVs continue to offer unparallel opportunities with significant translational implications for various neurological disorders. Significance Statement Extracellular vesicles present a less invasive liquid biopsy approach in the diagnosis and prognosis of various neurological disorders. Characterizing these vesicles in biofluids holds the potential to yield valuable molecular information, thereby significantly impacting the development of novel biomarkers for various neurological disorders. This paper has reviewed the methodology employed to isolate extracellular vesicles derived from various brain cells in biofluids, their utility in enhancing the molecular understanding of neurodegeneration, and the potential challenges in this research field.

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MicroRNAs from extracellular vesicles as a signature for Parkinson's disease

Cited by 15 publications

References 11 publications

Multi‐omic landscaping of human midbrains identifies disease‐relevant molecular targets and pathways in advanced‐stage Parkinson's disease

Multi‐omic landscaping of human midbrains identifies disease‐relevant molecular targets and pathways in advanced‐stage Parkinson's disease

Integrative analysis of DNA methylation and gene expression data for the diagnosis and underlying mechanism of Parkinson’s disease

Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust

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