Frontiers in Aging, Год журнала: 2023, Номер 4
Опубликована: Июнь 1, 2023
Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). characterized by progressive cognitive decline, memory loss, and neuropsychiatric behavioral symptoms, accounting most of the reported dementia cases. This now becoming major challenge burden on modern society, especially with aging population. Over last few decades, significant understanding pathophysiology AD has been gained studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, neuroinflammation. review focuses role non-canonical secondary structures DNA/RNA G-quadruplexes (G4s, G4-DNA, G4-RNA), G4-binding proteins (G4BPs), helicases, their roles in AD. Being critically important cellular function, G4s are involved regulation DNA RNA processes, replication, transcription, translation, localization, degradation. Recent studies have also highlighted G4-DNA’s inducing double-strand breaks that cause genomic instability G4-RNA’s participation regulating stress granule formation. emphasizes significance processes how homeostatic imbalance may contribute to
Язык: Английский
Процитировано
23Pleiotropic genetic architecture and novel loci for C-reactive protein levels
Nature Communications, Год журнала: 2022, Номер 13(1)
Опубликована: Ноя. 14, 2022
Abstract C-reactive protein is involved in a plethora of pathophysiological conditions. Many genetic loci associated with are annotated to lipid and glucose metabolism genes supporting common biological pathways between inflammation metabolic traits. To identify novel pleiotropic loci, we perform multi-trait analysis genome-wide association studies on levels along cardiometabolic traits, followed by series silico analyses including colocalization, phenome-wide Mendelian randomization. We find 41 19 gene sets various effects. Additionally, variants colocalize risk factors 12 them display unexpected discordant effects the shared traits which translated into associations clinical outcomes subsequent studies. Our findings provide insights mechanisms underlying metabolism, representing potential preventive therapeutic targets.
Язык: Английский
Процитировано
37RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Март 3, 2024
Abstract Tau aggregation is a defining feature of neurodegenerative tauopathies, including Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. This involves the liquid–liquid phase separation (LLPS) Tau, followed by its sol–gel transition, representing crucial step in aggregate formation both vitro vivo . However, precise cofactors influencing transition under physiological conditions (e.g., ion concentration temperature) remain unclear. In this study, we unveil that nucleic acid secondary structures, specifically RNA G-quadruplexes (rG4s), calcium ions (Ca 2+ ) synergistically facilitated human mimic intracellular (140 mM KCl, 15 NaCl, 10 MgCl 2 at 37□ presence molecular crowding reagents, formed stable liquid droplets through LLPS, maintaining fluidity for 24 h conditions. Notably, cell-derived promoted with G4-forming emerging as factor. Surprisingly, polyanion heparin did not elicit similar response, indicating distinct mechanism rooted electrostatic interactions. Further exploration underscored significance Ca , which accumulate intracellularly during neurodegeneration, additional promoting after h. Importantly, our findings demonstrate rG4s enhance within 1 when introduced to droplets. conclusion, study illuminates pivotal roles offering insights into potential triggers tauopathy.
Язык: Английский
Процитировано
6The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome
Journal of Clinical Medicine, Год журнала: 2024, Номер 13(5), С. 1338 - 1338
Опубликована: Фев. 27, 2024
: Individuals with Down syndrome (DS) exhibit an almost complete penetrance of Alzheimer's disease (AD) pathology but are underrepresented in clinical trials for AD. The Tau protein is associated microtubule function the neuron and crucial normal axonal transport. In several different neurodegenerative disorders, misfolding leads to hyper-phosphorylation (p-Tau), which may seed bystander cells spread. This review focused on current findings regarding p-Tau its potential as a "prion-like" spreader. It also considers consequences leading AD, particularly individuals syndrome.
Язык: Английский
Процитировано
5DExH-box helicase 9 modulates hippocampal synapses and regulates neuropathic pain
iScience, Год журнала: 2024, Номер 27(2), С. 109016 - 109016
Опубликована: Янв. 25, 2024
Experimental studies have shown that neuropathic pain impairs hippocampal synaptic plasticity. Here, we sought to determine the underlying mechanisms responsible for changes in painful mouse neurons. Beyond demonstrating proof-of-concept location of DExH-box helicase 9 (DHX9) nucleus, found it did exist cytoplasm and DHX9 depletion resulted structural functional at synapses hippocampus. A decrease was observed hippocampus after peripheral nerve injury; overexpression significantly alleviated nociceptive responses improved anxiety behaviors. Mimicking evoked spontaneous behavioral symptoms emotion naïve mice. Mechanistically, bound
Язык: Английский
Процитировано
4Loss of DHX36/G4R1, a G4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 3, 2025
SUMMARY G-quadruplexes (G4s) are four-stranded alternative secondary structures formed by guanine-rich nucleic acids and prevalent across the human genome. G4s enzymatically resolved using specialized helicases. Previous in vitro studies showed that DEAH-box Helicase 36 (DHX36/G4R1/RHAU), has highest specificity affinity for G4 structures. Here, mapping genome-wide DNA double-strand breaks (DSBs), we demonstrate knockout (KO) of DHX36 helicase increases DSB enrichment at sites presence motif is a significant mediator genome instability regulatory regions. The loss corresponds with upregulation NF-κB transcriptional programs, culminating production secretion proinflammatory cytokines. Loss expression results an increase innate immune signaling stimulator interferon response cGAMP interactor 1 ( STING1 ) activation genes involved pathways. Importantly, higher levels mRNA B-cell acute lymphoblastic leukemia correlate improved overall survival relative to lower , highlighting its critical role preserving integrity cellular level context cancer.
Язык: Английский
Процитировано
0Exploring the Role of G-Quadruplex DNA, and their Structural Polymorphism, in Targeting Small Molecules for the Design of Anticancer Therapeutics: Progress, Challenges, and Future Directions
Biochimie, Год журнала: 2025, Номер unknown
Опубликована: Апрель 1, 2025
Язык: Английский
Процитировано
0Exploring the biological roles of DHX36, a DNA/RNA G-quadruplex helicase, highlights functions in male infertility: A comprehensive review
International Journal of Biological Macromolecules, Год журнала: 2024, Номер 268, С. 131811 - 131811
Опубликована: Апрель 25, 2024
Язык: Английский
Процитировано
3Liquid-Liquid Phase Separation of the DEAD-Box Cyanobacterial RNA Helicase Redox (CrhR) into Dynamic Membraneless Organelles in Synechocystis sp. Strain PCC 6803
Applied and Environmental Microbiology, Год журнала: 2023, Номер 89(4)
Опубликована: Март 15, 2023
Compartmentalization of macromolecules into discrete non-lipid-bound bodies by liquid-liquid phase separation (LLPS) is a well-characterized regulatory mechanism frequently associated with the cellular stress response in eukaryotes. In contrast, formation and importance similar complexes just becoming evident bacteria. Here, we identify LLPS as which DEAD-box RNA helicase, cyanobacterial helicase redox (CrhR), compartmentalizes dynamic membraneless organelles temporal spatial manner to abiotic cyanobacterium Synechocystis sp. strain PCC 6803. Stress conditions induced CrhR form single crescent localized exterior thylakoid membrane, indicating that this region crucial domain response. These crescents rapidly dissipate upon alleviation conditions. Furthermore, aggregation was mediated an RNA-dependent reaction. We propose condensation performs roles metabolism, enabling rapid adaptation photosynthetic apparatus environmental stresses. results expand our understanding role functional compartmentalization helicases thus processing LLPS-mediated protein bacterial stress. IMPORTANCE Oxygen-evolving cyanobacteria evolved ~3 billion years ago, performing fundamental biogeochemical evolution early Earth continue perform nutrient cycling primary productivity today. The phylum consists diverse species flourish heterogeneous environments. A prime driver for survival ability alter performance shifting these organisms continuously encounter. This study demonstrated stresses elicit dramatic changes localization structural organization membrane. changes, (LLPS)-mediated mechanism, reveal novel can compartmentalize activity ribonucleoprotein organelles. have significant consequences changing
Язык: Английский
Процитировано
6Small-molecule-based regulation of gene expression in human astrocytes upon both positive and negative actuations of G-quadruplex control systems
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Фев. 21, 2024
A great deal of attention is currently being paid to strategies aiming at uncovering the biology four-stranded nucleic acid structure G-quadruplex (G4) via their stabilization in cells using G4-specific ligands. The conventional definition chemical implies that a complete assessment G4 can only be achieved through implementation complementary approach involving destabilization cellular G4s by ad hoc molecular effectors. We report here on an unprecedented comparison consequences pyridostatin (PDS) and phenylpyrrolocytosine (PhpC) both transcriptome- proteome-wide scales patient-derived human brain cells. Our results show PDS triggers dysregulation many circuitries, most drastic effects originating downregulation 354 transcripts 158 proteins primarily involved RNA transactions. In contrast, PhpC modulates landscapes far more focused manner with upregulation 295 mostly transactions as well, thus mirroring PDS. study first its kind extent G4-associated circuitries systematically pitting effect against direct unbiased manner.
Язык: Английский
Процитировано
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