The potential of using blood circular RNA as liquid biopsy biomarker for human diseases

Protein & Cell, Journal Year: 2020, Volume and Issue: 12(12), P. 911 - 946

Published: Nov. 1, 2020

Abstract Circular RNA (circRNA) is a novel class of single-stranded RNAs with closed loop structure. The majority circRNAs are formed by back-splicing process in pre-mRNA splicing. Their expression dynamically regulated and shows spatiotemporal patterns among cell types, tissues developmental stages. CircRNAs have important biological functions many physiological processes, their aberrant implicated human diseases. Due to high stability, becoming promising biomarkers diseases, such as cardiovascular autoimmune diseases cancers. In this review, we focus on the translational potential using blood liquid biopsy for We highlight abundant expression, essential significant correlations various components peripheral blood, including whole cells extracellular vesicles. addition, summarize current knowledge circRNA disease diagnosis or prognosis.

Language: Английский

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Autophagy‐associated non‐coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(5)

Published: May 1, 2024

Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in substantia nigra pars compacta. The precise etiology PD remains unclear, but emerging evidence suggests significant role for disrupted autophagy-a crucial cellular process maintaining protein and organelle integrity.

Language: Английский

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Circular RNAs in neurological conditions – computational identification, functional validation, and potential clinical applications

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Non-coding RNAs (ncRNAs) have gained significant attention in recent years due to advancements biotechnology, particularly high-throughput total RNA sequencing. These developments led new understandings of non-coding biology, revealing that approximately 80% regions the genome possesses biochemical functionality. Among ncRNAs, circular (circRNAs), first identified 1976, emerged as a prominent research field. CircRNAs are abundant most human cell types, evolutionary conserved, highly stable, and formed by back-splicing events which generate covalently closed ends. Notably, circRNAs exhibit high expression levels neural tissue perform diverse functions, including acting molecular sponges for microRNAs, interacting with RNA-binding proteins regulate their availability activity, modulating transcription splicing, even translating into functional peptides some cases. Recent computational experimental methods enhanced our ability identify validate circRNAs, providing valuable insights biological roles. This review focuses on circRNA they related neuropsychiatric neurodegenerative conditions. We also explore potential applications clinical diagnostics, therapeutics, future directions. remain relatively underexplored area context neurological disorders. However, emerging evidence supports role critical players etiology mechanisms conditions such schizophrenia, bipolar disorder, major depressive Alzheimer’s disease, Parkinson’s disease. findings suggest may provide novel framework contributing dysfunctions underpinning these complex

Language: Английский

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A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(9)

Published: July 26, 2020

Resource26 July 2020Open Access Transparent process A Parkinson's disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress Mor Hanan Department of Biological Chemistry, The Institute Life Sciences, Hebrew University Jerusalem, Israel Edmond Lily Safra Center for Brain Search more papers by this author Alon Simchovitz Nadav Yayon Shani Vaknine Roni Cohen-Fultheim Mina Everard Goodman Faculty Bar-Ilan University, Ramat Gan, Miriam Karmon Nimrod Madrer Talia Rohrlich Genetics, Moria Maman Estelle R Bennett David S Greenberg Eran Meshorer Erez Y Levanon orcid.org/0000-0002-3641-4198 Hermona Soreq Corresponding Author [email protected] orcid.org/0000-0002-0955-526X Sebastian Kadener orcid.org/0000-0003-0080-5987 Biology Department, Brandeis Waltham, MA, USA Information Hanan1,2, Simchovitz1,2, Yayon1,2, Vaknine1,2, Cohen-Fultheim3, Karmon3, Madrer1,2, Rohrlich2,4, Maman2,4, Bennett1,2, Greenberg1,2, Meshorer2,4, Levanon3, *,1,2 *,1,5 1Department 2The 3Mina 4Department 5Biology *Corresponding author. Tel: +972 548820629; E-mail: EMBO Mol Med (2020)12:e11942https://doi.org/10.15252/emmm.201911942 Correction(s) article stress06 November 2020 PDFDownload PDF text main figures. Peer ReviewDownload summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Circular RNAs (circRNAs) are brain-abundant mostly unknown functions. To seek their roles in (PD), we generated an RNA sequencing resource several brain region tissues from dozens PD control donors. In healthy substantia nigra (SN), circRNAs accumulate age-dependent manner, but SN correlation is lost total number reduced. contrast, levels increased other studied regions patients. We also found increase individuals. CircSLC8A1 carries 7 binding sites miR-128 strongly bound microRNA effector protein Ago2. Indeed, targets individuals, suggesting that regulates function and/or activity. cultured cells exposed stress-inducing agent paraquat were decreased treated with neuroprotective antioxidant regulator drug Simvastatin. Together, our work links stress-related Parkinsonism suggests further exploration its molecular PD. Synopsis human brains, circRNA specific inversely correlate editing. reduced accumulation age lost. increases oxidation, Ago2 sponges miR128 targets, modulating neuronal survival aging. CircRNA be region-specific editing Alu repeats. Disease (PD) SN, individuals Paraquat. paper explained Problem leading neurodegenerative movement disorder; however, mechanisms underlying cellular degeneration brains remain poorly understood. recently discovered class expression patterns diseased largely unknown. Results used very deep explore three different patients, (SN) where dopaminergic neurons die brain, amygdala which responds stressful situations at large temporal gyrus harboring routes nuclei cortex. correlated Also, identified not focused experiments on CircSLC8A1, originates Ca2+ regulating SLC8A1 gene. Notably, one microRNA, miR-128, Correspondingly, activity miR-128. Impact Our findings establish expressed reveal previously expression, pathology, call exploring implications addressing initiation processes. Introduction second most common disorder, affecting 1–2% population over 65 (Farrer, 2006; Farrer et al, 2006). characterized progressive loss attributed multi-leveled elusive complex interactions genetic susceptibilities, male sex, environmental toxins, mitochondrial dysfunction, imbalanced signaling processes Consequent depletion nigrostriatal pathway striatal dopamine then lead prominent motor symptoms bradykinesia, hypokinesia, rigidity, resting tremor, postural stability. risk factors include exposure herbicides, pesticides, metal-derived substances (Collier 2011). major hallmark intracellular deposits (named Lewy bodies) primarily composed precipitates alpha-synuclein (SNCA) protein. Much knowledge genes pathways involved derives studies inherited forms disease. Those have been associated mutations (SNCA), synaptic function, as well Parkin Pink1, mitochondria quality control, DJ-1, response kinase LRRK2 [4]. onset families these 20 50, considerably earlier than years age, typical sporadic Additionally, involves massive changes metabolism (La Cognata 2015), both (Liu 2017) patients' leukocytes (Soreq 2008, 2012, 2014; 2020), contributions circular risks so far remained unexplored. rediscovered type co-transcriptional circularization exons spliceosome named back-splicing (Memczak 2013; Ashwal-Fluss Jeck Sharpless, Li 2018; Kristensen 2019). They flies, nematodes, mice (Westholm Gruner 2016; Cortes-Lopez 2018), some them enriched synapses dendrites (Rybak-Wolf 2015; Veno You 2015). Most known derived RNA-polymerase II transcription coding genes, structure makes resistant exonucleases hence exceptionally stable molecules compared canonical mRNA (Jeck 2013). Hence, can potentially become biomarkers follow-up treatment efficacy or new therapeutics (Zhang 2018). While thousands described, only few has elucidated. These circCDR1as, abundant mammalian circRNA. CircCDR1as antisense strand cerebellar degeneration-related 1 (CDR1) gene highly (Hansen It binds miR Argonaute2 (Ago2) harbors 73 miR-7 Memczak Initially, it was though CDR1as degrades miR-7. However, knockout results lower, higher miRNA, stability way (Piwecka 2017). This likely non-coding Cyrano (Guo Kleaveland shown functional vivo flies (Holdt Chen 2017; 2017a,2017b; Pamudurti proposed variety functions RBP transport (Ashwal-Fluss 2014), rRNA maturation, miRNA stabilization 2016). Moreover, subset translated no products (Legnini Yang Liang Interestingly, reports suggested disorders Alzheimer's amyotrophic lateral sclerosis (Lukiw, Errichelli Shi Dube Supporting notion, many features, suggest potential demise. called establishing role intriguing transcripts could addressed. production regulated hyper-editing events—higher beyond transcriptome alignment (Porath Ivanov Rybak-Wolf As 99% A-to-I humans occurs elements, those elements may serve measure global (Levanon 2004). transposable genome (over million copies), originated inserted opposite orientations form dsRNA structures, providing substrate adenosine deaminases (ADAR proteins). flanked introns contain repeats postulated mediate generation (Ivanov Multiple pairing events competition formation alternative same locus 2014a,2014b). ADAR negatively correlates neural tissue cell lines regulation complex. On hand, relative location (or repeats) key determining how modulates biogenesis DHX9, helicase inverted-repeat unwinds secondary represses abundance (Aktas whether such relate yet investigated. address determine biomark disease, comprehensively profiled individuals: much PD-related demise takes place, medial temporalis (MTG), (AMG), controls acute accompany Comparing patients matched apparently aged elements. Having significantly upregulated selected in-depth example relates PD-inducing stress. sum, provides important studying demonstrates miss-regulated genomic profiles particular changed PD, sequenced rRNA-depleted RNA-seq libraries AMG, MTG (Fig EV1A–D; see Dataset EV1 clinical data donors). analyzed included 27 42 samples (libraries prepared RIN > 6.5, excluded low circRNAs; Appendix Fig S1E–H). relatively set assisted dealing individual heterogeneity characteristic (Barbash level (50 M reads per sample average; EV1I, EV2), allowing reliable simultaneous detection quantification mRNAs, long (lncRNAs) circRNAs. bioinformatics pipeline identify annotate mRNAs Click here expand figure. Figure EV1. Tissues retrieved experimental in-house methodology A. origin NBB detailing each area. B. Average plot frozen tissues. C. Library preparation steps (see details Materials Methods). D. TapeStation run. E–G. Number detected all 3 regions. Samples < 5,000 removed analysis. H. I. tissue. Download figure PowerPoint An initial analysis non-supervised hierarchical clustering indicated substantial AMG failed distinguish (Figs 11A B, EV2A). reflected individuals; pronounced specificity dominate gender, Braak stage differences, severity, possibly impact diverse medications relevant (Braak 2003). Unlike samples, enabled better separation 11C EV2B–D). might reflect bigger differences due SN. tyrosine hydroxylase (TH) (t-test P = 0.025; 11D), compatible decrease upon 1. indicate multicellular tissues: (blue), (green), (red). Non-supervised heatmap indicates controls. red. PCA (green) (blue). qPCR validation TH controls, normalized beta-actin mRNA. t-test *P 0.025. Data presented mean ± SD. n 18 CT 24 E. Top GO DE vs corresponding logP values, Wald test (DEseq2 analysis). F, G. Venn diagrams demonstrating type-specific tissues, up/down arrows groups regulated. Module–trait relationship WGCNA showing corrected values (in brackets) module (indicated colors) related external traits (disease condition, region, sex). Correlation p value calculated package. Module membership vs. significance modules reflecting traits: condition (reflected brown red modules), (the blue module), sex cyan regression-based 8 15 13 10 J. Significant terms emerged blue, red, log Fisher's exact value. EV2. QC, Substantia heatmap, represented colors, marked color key: Reduction light green elevation blue. C, MTG. Sample dendrogram classification sample. F. Cluster genes. G, log2 fold change −log splicing SD, Walt Global following correction composition (for microglia, astrocytes, neurons, Methods) (e.g., SNCA, TH, DNAJC6, SYNJ1, GBA, SLC6A3) (corrected 0.00048), synapse 2.06E-05) neurodegeneration 0.0017; Miller 2004; Zhang 2005; Moran Simunovic 2009; Lewis Cookson, 2012). Gene Ontology (GO) enrichment differentially (DE) junctions, vesicle 8.52E-04), ion 1.37E-04), biosynthetic 0.0198), 11E, EV3 FDR 0.01 term analysis, EV4 shows detailed terms). next utilized single-cell types expressing (McKenzie 11F G) types, endothelial cells, oligodendrocytes, astrocytes proportion microglia. neuron-specific predictably showed decreases (63 14 chi-square test, 3.5E-12), whereas oligodendrocytes microglia-expressed tendency (24 12 2 brains), fractions elevated inflammation. putative co-regulation performed weighted network (WGCNA; Langfelder Horvath, 2008). closely altered patterns, creating intra-related variability scores EV2E F EV5). Genes clustered into colors 11H, left scale), assessed relationships calculating trait 11H). measured correlations memberships closeness gene's modules. certain module–trait relationships, (PD control), classification,

Language: Английский

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Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(24), P. 9582 - 9582

Published: Dec. 16, 2020

Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration RNA metabolism a key factor etiopathogenesis these complex disorders. Non-coding RNAs are major contributor to human transcriptome and particularly abundant central nervous system, where they have been proposed be involved onset development NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs pseudogenes) share common functionality their ability regulate gene expression by modulating miRNAs phenomenon known competing endogenous mechanism. Moreover, found body fluids presence concentration could serve potential non-invasive biomarkers In this review, we summarize ceRNA networks described Alzheimer’s disease, Parkinson’s multiple sclerosis, amyotrophic lateral sclerosis spinocerebellar ataxia type 7, discuss Although numerous studies carried out, further research needed validate interactions between alterations editing provide specific ceRNET profiles for disorders, paving way better understanding diseases.

Language: Английский

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The role of noncoding RNAs in Parkinson’s disease: biomarkers and associations with pathogenic pathways

Journal of Biomedical Science, Journal Year: 2021, Volume and Issue: 28(1)

Published: Nov. 18, 2021

Abstract The discovery of various noncoding RNAs (ncRNAs) and their biological implications is a growing area in cell biology. Increasing evidence has revealed canonical noncanonical functions long small ncRNAs, including microRNAs, ncRNAs (lncRNAs), circular RNAs, PIWI-interacting tRNA-derived fragments. These have the ability to regulate gene expression modify metabolic pathways. Thus, they may important roles as diagnostic biomarkers or therapeutic targets diseases, neurodegenerative disorders, especially Parkinson’s disease. Recently, through diverse sequencing technologies wide variety bioinformatic analytical tools, such reverse transcriptase quantitative PCR, microarrays, next-generation long-read sequencing, numerous been shown be associated with In this review article, we will first introduce biogenesis different pros cons detection platforms reproducibility tools discussed second part. Finally, recent PD-associated association diagnosis pathophysiology PD are reviewed, microRNAs that transported by exosomes biofluids particularly emphasized.

Language: Английский

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Several miRNAs derived from serum extracellular vesicles are potential biomarkers for early diagnosis and progression of Parkinson’s disease

Translational Neurodegeneration, Journal Year: 2021, Volume and Issue: 10(1)

Published: July 28, 2021

Abstract Background Blood-based test for predicting disease progression and early diagnosis of Parkinson’s (PD) is an unmet need in the clinic. The profiles microRNAs (miRNAs) are regarded as potential diagnostic biomarkers human diseases, whereas miRNAs periphery susceptible to influence various components. MiRNAs enriched serum extracellular vesicles (EVs) have demonstrated disease-specific advantages due their high abundance, stability resistance degradation. This study was aimed screen differentially expressed EV-derived between healthy controls PD patients aid PD. Methods A total 31 72 with a at different Hoehn Yahr stages Tangdu Hospital were included. In total, 185 obtained through RNA sequencing EVs well edgeR t -test analyses. Subsequently, weighted gene co-expression network analysis (WGCNA) utilized identify commonly all by constructing connections modules, specifically each stage functional enrichment analysis. After aligning these PD-related Human miRNA Disease Database, screened further validated receiver operating characteristic (ROC) curves quantitative real-time polymerase chain reaction (qRT-PCR) using peripheral blood from 40 more participants. Results WGCNA showed that 4 associated 13 Of 17 miRNAs, 7 ROC curve verified participants qRT-PCR. Six both methods, which included 2 Conclusions 6 hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-199a-3p, hsa-miR-28-5p, hsa-miR-22-5p hsa-miR-151a-5p, may potentially be used populations.

Language: Английский

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Epigenetic Regulation of Neuroinflammation in Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4956 - 4956

Published: May 7, 2021

Neuroinflammation is one of the most significant factors involved in initiation and progression Parkinson’s disease. PD a neurodegenerative disorder with motor disability linked various complex diversified risk factors. These trigger myriads cellular molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, neurotoxic substances that induce selective neurodegeneration dopamine neurons. This neuronal damage activates immune system, including glial cells inflammatory cytokines, to neuroinflammation. The transition acute chronic neuroinflammation enhances susceptibility inflammation-induced dopaminergic neuron damage, forming vicious cycle prompting an individual development. Epigenetic mechanisms recently have been at forefront regulation neuroinflammatory PD, proposing new dawn for breaking this cycle. review examined core epigenetic activation phenotypic transformation mediated PD. We found do not work independently, despite being coordinated each other activate pathways. In regard, we attempted find synergic correlation contribution these modifications pathways broaden canvas underlying pathological Moreover, study highlighted dual characteristics (neuroprotective/neurotoxic) marks, which may counteract pathogenesis make them potential candidates devising future diagnosis treatment.

Language: Английский

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Differentially Expressed Circular RNAs in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease

Movement Disorders, Journal Year: 2021, Volume and Issue: 36(5), P. 1170 - 1179

Published: Jan. 12, 2021

Abstract Background New noninvasive and affordable molecular approaches that will complement current practices increase the accuracy of Parkinson's disease (PD) diagnosis are urgently needed. Circular RNAs (circRNAs) stable noncoding accumulate with aging in neurons increasingly shown to regulate all aspects neuronal development function. Objectives Τhe aims this study were identify differentially expressed circRNAs blood mononuclear cells patients idiopathic PD explore competing endogenous RNA networks affected. Methods Eighty‐seven initially selected based on relatively high gene expression human brain. More than half these readily detectable using real‐time reverse transcription‐polymerase chain reaction. Comparative analysis was then performed from 60 control subjects PD. Results Six significantly down‐regulated The classifier best distinguished consisted four an area under curve 0.84. Cross‐linking immunoprecipitation‐sequencing data revealed RNA‐binding proteins bound by most deregulated include neurodegeneration‐associated FUS, TDP43, FMR1, ATXN2. MicroRNAs predicted be sequestered have Gene Ontology categories “protein modification” “transcription factor activity” mostly enriched. Conclusions This is first identifies specific may serve as diagnostic biomarkers for Because they highly brain derived genes essential functions, also hint pathways © 2021 Biomedical Research Foundation, Academy Athens. Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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CircSV2b participates in oxidative stress regulation through miR-5107-5p-Foxk1-Akt1 axis in Parkinson's disease

Redox Biology, Journal Year: 2022, Volume and Issue: 56, P. 102430 - 102430

Published: Aug. 12, 2022

As a novel type of non-coding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have indicated that dysregulation circRNAs was related to neurological diseases. However, the biogenesis, regulation, function, and mechanism Parkinson's disease (PD) remain largely unclear. In this study, thirty-three differentially (DECs) were detected by RNA-sequencing between MPTP-induced PD mice model wild-type mice. Quantitative real-time PCR used determine RNA level DECs striatum (STR), substantia nigra pars compacta (SNpc), serum exosomes, it found circSV2b downregulated Then, functional experiments vivo employed explore effect PD. For dual-luciferase reporter, fluorescence situ hybridization (FISH), immunoprecipitation (RIP), pull-down, gene editing, CUT & Tag performed vitro confirm directly sponged miR-5107-5p alleviated suppression expression target Foxk1, then positively regulated Akt1 transcription. vivo, mechanistic analysis demonstrated overexpression resisted oxidative stress damage through ceRNA-Akt1 axis models. Taken together, these findings suggested miR-5107-5p-Foxk1-Akt1 might serve as key treatment, highlighted significant change exosomes. Therefore, be biomarker for diagnosis treatment

Language: Английский

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