Validation of Differentially Expressed Brain-Enriched microRNAs in the Plasma of Parkinson’s Disease Patients

Ravanidis, Stylianos; Bougea, Anastasia; Papagiannakis, Nikolaos; Koros, Christos; Simitsi, Athina Maria; Pachi, Ioanna; Breza, Marianthi; Stefanis, Leonidas; Doxakis, Epaminondas

doi:10.21203/rs.3.rs-33785/v1

Cited by 3 publications

(2 citation statements)

References 57 publications

(67 reference statements)

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“…These data, however, have not been experimentally validated. Some reports indicate, an in silico correlation between miR-136-3p or miR-369-5p and TGF-β1 pathway, although to our knowledge, no other published studies showed regulation of miR-136-3p, miR-369-5p, or miR-561-5p by TGF-β1 [71,72].…”

Section: Ace2 and Tgf-β1 Signaling In The Airwaymentioning

confidence: 71%

TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis

Hejenkowska,

Mitash,

Donovan

et al. 2023

J Innate Immun

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SARS-CoV-2 utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin-converting enzyme 2 (ACE2). Decreased cell surface density of ACE2 contributes to mortality during COVID-19. Studies published early during the pandemic reported that people with cystic fibrosis (PwCF) treated with the high efficiency CFTR modulators ETI (elexacaftor-tezacaftor-ivacaftor) had higher ACE2 levels and milder COVID-19 symptoms, compared to people without CF. Subsequent studies did not confirm these findings. TGF-β1 gene polymorphisms associated with higher TGF-β1 levels, present in approximately 40% of CF patients, lead to more severe CF lung disease. To understand whether TGF-β1 modulates COVID-19 severity by affecting ACE2 levels in the airway, we performed small RNAseq and microRNA profiling and identified pathways uniquely affected by TGF-β1, including those associated with SARS-CoV-2 invasion. TGF-β1 inhibited ACE2 expression by miR-136-3p and miR-369-5p. ACE2 levels were higher in CF bronchial epithelial cell models. ETI did not prevent TGF-β1 inhibition of ACE2. Finally, TGF-β1 reduced the interaction between ACE2 and RBD by lowering ACE2 levels and its binding to RBD. Our data demonstrate novel mechanism whereby TGF-β1 inhibition of ACE2 in CF and non-CF bronchial epithelia may modulate SARS-CoV-2 pathogenicity and COVID-19 severity. By reducing ACE2 levels, TGF-β1 may decrease entry of SARS-CoV-2 into host cells while hindering recovery from COVID-19 due to loss of anti-inflammatory effects of ACE2.

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Section: Ace2 and Tgf-β1 Signaling In The Airwaymentioning

confidence: 71%

TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis

Hejenkowska,

Mitash,

Donovan

et al. 2023

J Innate Immun

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“…There is accumulating evidence that the miRNA landscape is dysregulated in epilepsy [29,[40][41][42][43] and other brain diseases [44][45][46][47][48], raising prospects for treating disease by over-or underexpressing key miRNAs. Key experimental tools for miRNA targeting are summarised in Figure 1.…”

Section: 'Drugging' Mirnasmentioning

confidence: 99%

Opportunities and challenges for microRNA-targeting therapeutics for epilepsy

Morris

O’Brien²,

Henshall

2021

Trends in Pharmacological Sciences

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Epilepsy is a common and serious neurological disorder characterised by recurrent spontaneous seizures. Frontline pharmacotherapy includes small-molecule antiseizure drugs that typically target ion channels and neurotransmitter systems, but these fail in 30% of patients and do not prevent either the development or progression of epilepsy. An emerging therapeutic target is microRNA (miRNA), small noncoding RNAs that negatively regulate sets of proteins. Their multitargeting action offers unique advantages for certain forms of epilepsy with complex underlying pathophysiology, such as temporal lobe epilepsy (TLE). miRNA can be inhibited by designed antisense oligonucleotides (ASOs; e.g., antimiRs). Here, we outline the prospects for miRNA-based therapies. We review design considerations for nucleic acid-based approaches and the challenges and next steps in developing therapeutic miRNA-targeting molecules for epilepsy.Current versus future drugs for epilepsy: the need for change Epilepsy (see Glossary) is a common, often life-long brain disease characterised by recurrent, spontaneous seizures that are the result of hypersynchronous discharges of neurons [1]. There are more than 20 different small-molecule drugs in clinical use that reduce or prevent seizures in people with epilepsy. This is a remarkable achievement, certainly relative to the lack of treatments for many neurological disorders, and is owed to a solid mechanistic understanding of how seizures arise through imbalances between excitation and inhibition and the availability of good disease models that identify molecules with antiexcitability properties [2]. However, antiseizure drugs likely do not substantially alter the underlying pathophysiology of epilepsy, and one-third of patients are refractory to current treatments. Addressing this treatment gap is a major priority [1,3], and, increasingly, researchers are looking at substantially different targets.Acquired forms of epilepsy, such as TLE, have a limited genetic basis and probably arise from an earlier brain insult that leads to select cell loss, gliosis, neuroinflammation, and vascular and microscopic as well as macroscopic reorganisation of brain networks [4,5]. Because of this, single targets, such as ion channels, may be unsuitable or insufficient to overcome drug resistance, achieve disease modification, or prevent epileptogenesis [6] (Box 1). Novel approaches that can modify multiple targets may be necessary. Additionally, suitable target(s) may not reside on the outside of neurons but instead be intracellular. Both challenges could be solved by using RNAbased medicines such as ASOs, which offer virtually unlimited potential to target any gene, and small noncoding RNAs called microRNAs (miRNAs), which are 'multi-pathway' regulatory molecules (for a recent review on the general topic of RNA medicines, the reader is referred elsewhere [7]).The first miRNA medicine reached human trials in 2013 [8], and several others are in clinical testing. The versatility of ASO-based medicines was elegantly dem...

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Differentially expressed circular RNAs in peripheral blood mononuclear cells of PD patients

Ravanidis

Bougea

Karampatsi

et al. 2020

Preprint

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BackgroundNew noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of PD diagnosis are urgently needed. CircRNAs are highly stable non-coding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function.ObjectivesThe aims of the present study were to identify differentially expressed circRNAs in PBMCs of idiopathic PD patients and explore the competing endogenous RNA networks affected.MethodsEighty-seven circRNAs were initially selected based on relatively high gene expression in the human brain. Over half of these were readily detectable in PBMCs using RT-qPCR. Comparative expression analysis was then performed in PBMCs from sixty controls and sixty idiopathic subjects with PD.ResultsSix circRNAs derived from MAPK9, HOMER1, SLAIN1, DOP1B, REPS1, and PSEN1 transcripts were significantly downregulated in PD patients. The classifier that best distinguished PD consisted of four circRNAs with an AUC of 0.84. CLIP-Seq data revealed that the RNA binding proteins bound by most of the deregulated circRNAs include the neurodegeneration-associated FUS, TDP43, FMR1 and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs had the GOslim categories ‘Protein modification’, ‘Transcription factor activity’ and ‘Cytoskeletal protein binding’ mostly enriched.ConclusionsThis is the first study that identifies circRNAs deregulated in the peripheral blood of PD patients. They may serve as diagnostic biomarkers and since they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected.

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Validation of Differentially Expressed Brain-Enriched microRNAs in the Plasma of Parkinson’s Disease Patients

Cited by 3 publications

References 57 publications

TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis

TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis

Opportunities and challenges for microRNA-targeting therapeutics for epilepsy

Differentially expressed circular RNAs in peripheral blood mononuclear cells of PD patients

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