MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Май 31, 2024

Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination affected tissue, pathological changes reveal a loss synapses, misfolded proteins, and activation immune cells—all indicative disease progression—before severe clinical symptoms become apparent. Early detection NDs is crucial for potentially administering targeted medications may delay advancement. Given their complex pathophysiological features diverse symptoms, there pressing need sensitive effective diagnostic methods NDs. Biomarkers such as microRNAs (miRNAs) have been identified potential tools detecting these diseases. We explore pivotal role miRNAs in context NDs, focusing on Alzheimer’s disease, Parkinson’s Multiple sclerosis, Huntington’s Amyotrophic Lateral Sclerosis. The review delves into intricate relationship between aging highlighting structural functional alterations implications development. It elucidates how RNA-binding proteins implicated pathogenesis underscores importance investigating expression function aging. Significantly, exert substantial influence post-translational modifications (PTMs), impacting not just nervous system but wide array tissues types well. Specific found target involved ubiquitination de-ubiquitination processes, which play significant regulating protein stability. discuss link miRNA, PTM, Additionally, discusses significance biomarkers early detection, offering insights strategies.

Язык: Английский

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Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts

Journal of Cellular Physiology, Год журнала: 2022, Номер 237(4), С. 2169 - 2182

Опубликована: Янв. 19, 2022

Pathological fibrosis contributes to progression of various diseases, for which the therapeutic options are limited. Idiopathic pulmonary (IPF) is one such progressive and fatal interstitial fibrotic disease that often characterized by excessive accumulation extracellular matrix (ECM) proteins leading stiff lung tissue impaired gas exchange. However, molecular mechanisms underlying IPF remain largely unknown. In this study, we determined role Runt-related transcription factor 1 (RUNX1), an evolutionarily conserved factor, in differentiation human fibroblasts (HLFs) vitro animal model bleomycin (BLM)-induced fibrosis. We observed expression RUNX1 was significantly increased lungs BLM-injected mice as compared saline-treated mice. Furthermore, HLFs stimulated with transforming growth β (TGF-β) showed higher at both mRNA protein levels, compartmentalization nucleus. Inhibition (using siRNA) a significant reduction into myofibroblasts evidenced reduced alpha-smooth muscle actin (α-SMA), TGF-β ECM fibronectin (FN1), collagen 1A1 (COL1A1). Mechanistic studies revealed TGF-β-stimulated due enhanced stability through selective interaction RNA-binding profibrotic protein, antigen R (HuR). Collectively, our data demonstrate augments processes involved including collagen-synthesizing myofibroblasts. Our study suggests targeting could limit organ diseases abnormal deposition.

Язык: Английский

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RNA-Binding Proteins as Regulators of Internal Initiation of Viral mRNA Translation

Viruses, Год журнала: 2022, Номер 14(2), С. 188 - 188

Опубликована: Янв. 19, 2022

Viruses are obligate intracellular parasites that depend on the host’s protein synthesis machinery for translating their mRNAs. The viral mRNA (vRNA) competes with host to recruit translational machinery, including ribosomes, tRNAs, and limited eukaryotic translation initiation factor (eIFs) pool. Many viruses utilize non-canonical strategies such as targeting eIFs RNA elements known internal ribosome entry sites (IRESs) reprogram cellular gene expression, ensuring preferential of vRNAs. In this review, we discuss vRNA IRES-mediated initiation, highlighting role RNA-binding proteins (RBPs), other than canonical factors, in regulating activity.

Язык: Английский

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The main sources of molecular organization in the cell. Atlas of self-organized and self-regulated dynamic biostructures

Progress in Biophysics and Molecular Biology, Год журнала: 2025, Номер 195, С. 167 - 191

Опубликована: Янв. 11, 2025

Язык: Английский

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Simultaneous profiling of native-state proteomes and transcriptomes of neural cell types using proximity labeling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Abstract Deep molecular phenotyping of cells at transcriptomic and proteomic levels is an essential first step to understanding cellular contributions development, aging, injury, disease. Since proteome transcriptome level abundances only modestly correlate with each other, complementary profiling both needed. We report a novel method called simultaneous protein RNA –omics (SPARO) capture the cell type-specific simultaneously from in vitro vivo experimental model systems. This leverages ability biotin ligase, TurboID, biotinylate cytosolic proteins including ribosomal RNA-binding proteins, which allows enrichment biotinylated for proteomics as well protein-associated transcriptomics. validated this approach using well-controlled systems verify that proteomes transcriptomes obtained reflect ground truth, bulk transcriptomes. also show effect biological stimulus (e.g., neuroinflammatory activation by lipopolysaccharide) can be faithfully captured. applied obtain native-state two key neural types, astrocytes neurons, thereby validating application SPARO. Next, we used these data interrogate protein-mRNA concordance discordance across providing insights into groups processes exhibit uniform or patterns mRNA-protein discordance.

Язык: Английский

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ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

Biomolecules, Год журнала: 2022, Номер 12(3), С. 443 - 443

Опубликована: Март 13, 2022

Cellular functions are regulated through the gene expression program by transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, post-translational modifications (PTMs) proteins add another layer complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification cellular macromolecules, regulating multitude key functional processes as diverse DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune stress responses, cell survival. Additionally, due to emerging role in pathological processes, ADP-ribosyltransferases (ARTs), enzymes involved ADPr, attracting growing interest drug targets. In review, overview human ARTs their related biological provided, mainly focusing on regulation ADP-ribosyltransferase Diphtheria toxin-like (ARTD)-dependent functions. Finally, order unravel novel relationships, we propose analysis inventory clusters, including ARTDs, which share conserved sequences at 3′ untranslated regions (UTRs).

Язык: Английский

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FMRP modulates the Wnt signalling pathway in glioblastoma

Cell Death and Disease, Год журнала: 2022, Номер 13(8)

Опубликована: Авг. 18, 2022

Converging evidence indicates that the Fragile X Messenger Ribonucleoprotein (FMRP), which absent or mutated in Syndrome (FXS), plays a role many types of cancers. However, while FMRP roles brain development and function have been extensively studied, its involvement biology tumors remains largely unexplored. Here we show, human glioblastoma (GBM) biopsies, increased expression directly correlates with worse patient outcome. In contrast, reductions correlate diminished tumor growth proliferation GBM stem-like cells (GSCs) vitro cell culture model vivo mouse GSC xenografts. Consistently, levels promote proliferation. To characterize mechanism(s) by regulates proliferation, performed transcriptome analyses GSCs expressing high FMRP, these after knockdown FMRP. We show WNT signalling is most significantly enriched among published target genes involved ASD. find downregulate both canonical WNT/β-Catenin non-canonical WNT-ERK1/2 pathways, reducing stability several key transcription factors (i.e. β-Catenin, CREB ETS1) previously implicated modulation malignant features glioma cells. Our findings support for cancer progression, acting via regulation signalling.

Язык: Английский

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The mechanical regulation of RNA binding protein hnRNPC in the failing heart

Science Translational Medicine, Год журнала: 2022, Номер 14(672)

Опубликована: Ноя. 23, 2022

Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond ensuing biomechanical stress reexpressing fetal contractile proteins via transcriptional and posttranscriptional processes, such as alternative splicing (AS). Here, we demonstrate heterogeneous nuclear ribonucleoprotein C (hnRNPC) is up-regulated relocates sarcomeric Z-disc upon ECM pathological remodeling. We show this an active site localized translation, where associates with translation machinery. Alterations in hnRNPC expression, phosphorylation, localization can be mechanically determined affect AS mRNAs involved mechanotransduction cardiovascular diseases, including Hippo pathway effector Yes-associated protein 1. propose cardiac serves a switch RNA metabolism affecting associated regulatory spliceosome apparatus. These findings offer new insights on mechanism mRNA homeostatic mechanoregulation conditions.

Язык: Английский

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RNA-binding proteins that preferentially interact with 8-oxoG-modified RNAs: our current understanding

Biochemical Society Transactions, Год журнала: 2024, Номер 52(1), С. 111 - 122

Опубликована: Янв. 4, 2024

Cells encounter a variety of stresses throughout their lifetimes. Oxidative stress can occur via myriad factors, including exposure to chemical toxins or UV light. Importantly, these stressors induce changes (e.g. modifications) biomolecules, such as RNA. Commonly, guanine is oxidized form 8-oxo-7,8-hydroxyguanine (8-oxoG) and this modification disrupt plethora cellular processes messenger RNA translation stability. Polynucleotide phosphorylase (PNPase), heterogeneous nuclear ribonucleoprotein D (HNRPD/Auf1), poly(C)-binding protein (PCBP1/HNRNP E1), Y-box binding 1 (YB-1) have been identified four RNA-binding proteins that preferentially bind 8-oxoG-modified over unmodified All are native humans PNPase additionally found in bacteria. Additionally, under oxidative stress, cell survival declines mutants lack PNPase, Auf1, PCBP1, suggesting they critical the response. This mini-review captures current understanding HNRPD/Auf1, YB-1 mechanism has outlined so far by which recognize interact with RNAs.

Язык: Английский

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PRMT5-mediated arginine methylation of FXR1 is essential for RNA binding in cancer cells

Nucleic Acids Research, Год журнала: 2024, Номер 52(12), С. 7225 - 7244

Опубликована: Май 6, 2024

Abstract Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates gene expression. Here, we report post-translational modification FXR1 enhances binding with mRNAs is involved in cancer cell growth proliferation. Independent point mutations residues FXR1’s nuclear export signal (R386 R388) RGG (R453, R455 R459) domains prevent it from to RNAs form G-quadruplex (G4) RNA structures. Disruption G4-RNA structures by lithium chloride failed bind FXR1, indicating its preference for structure containing mRNAs. Furthermore, loss-of-function PRMT5 inhibited both vivo vitro, affecting protein stability, inhibiting activity Finally, enhanced crosslinking immunoprecipitation (eCLIP) analyses reveal binds G4-enriched mRNA targets such as AHNAK, MAP1B, AHNAK2, HUWE1, DYNC1H1 UBR4 controls expression cells. Our findings suggest PRMT5-mediated required RNA/G4-RNA binding, which Thus, structural characteristics affinity preferentially G4 regions provide new insights into molecular mechanism oral

Язык: Английский

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