Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions DOI Creative Commons
Leonardo D’Aiuto,

Jill K. Caldwell,

Terri G. Edwards

и другие.

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106804 - 106804

Опубликована: Янв. 1, 2025

Abnormal tau phosphorylation is a key mechanism in neurodegenerative diseases. Evidence implicates infectious agents, such as Herpes Simplex Virus 1 (HSV-1), co-factors the onset or progression of diseases, including Alzheimer's disease. This has led to divergence field regarding contribution viruses etiology Research indicates that may function risk factors driving disease rather than playing causative role. Investigating HSV-1 abnormal important for understanding role agents neurodegeneration. We generated cellular models acute, latent infection, and viral reactivation from latency cortical brain organoids investigated interplay between infection by employing human induced pluripotent stem cell (iPSC)-derived monolayer neuronal cultures organoids. Acute with strains 17syn+ KOS caused nuclear accumulation phosphorylated (p-tau) neurons neural precursor cells. Antivirals prevented p-tau. Viral was accompanied translocation Chromatin immunoprecipitation analysis indicated an interaction p-tau chromatin. A reduction abundance component speckles their loss organized morphology low host chromatin density regions observed, strain-specific differences. followed increase BRSKs TAOKs, kinases known phosphorylate tau. These findings show demonstrate ability activate mechanisms are observed

Язык: Английский

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids DOI Creative Commons
Kathryn R. Bowles, M. Catarina Silva, Kristen Whitney

и другие.

Cell, Год журнала: 2021, Номер 184(17), С. 4547 - 4563.e17

Опубликована: Июль 26, 2021

Язык: Английский

Процитировано

120

Tau liquid–liquid phase separation in neurodegenerative diseases DOI Creative Commons
Solomiia Boyko, Witold K. Surewicz

Trends in Cell Biology, Год журнала: 2022, Номер 32(7), С. 611 - 623

Опубликована: Фев. 15, 2022

Язык: Английский

Процитировано

117

Formation, function, and pathology of RNP granules DOI Creative Commons
Nina Ripin,

Roy Parker

Cell, Год журнала: 2023, Номер 186(22), С. 4737 - 4756

Опубликована: Окт. 1, 2023

Язык: Английский

Процитировано

82

Nuclear transport proteins: structure, function, and disease relevance DOI Creative Commons
Yang Yang,

Lu Guo,

Lin Chen

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 10, 2023

Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport a fundamental cellular process that regulates many macromolecules within nuclear or cytoplasmic compartments. In humans, approximately 60 are involved in transport, nucleoporins form membrane-embedded pore complexes, karyopherins cargoes through these Ran system ensure directed rapid transport. Many play additional essential roles mitosis, biomolecular condensation, gene transcription. Dysregulation linked to major human diseases such as cancer, neurodegenerative diseases, viral infections. Selinexor (KPT-330), an inhibitor targeting export factor XPO1 (also known CRM1), was approved 2019 treat two types blood cancers, dozens clinical trials ongoing. This review summarizes three decades research data this field but focuses on structure function individual from recent studies, providing cutting-edge holistic view role health disease. In-depth knowledge rapidly evolving has potential bring new insights into biology, pathogenic mechanisms, therapeutic approaches.

Язык: Английский

Процитировано

71

RNA dysregulation in neurodegenerative diseases DOI Creative Commons
Yini Li, Shuying Sun

The EMBO Journal, Год журнала: 2025, Номер 44(3), С. 613 - 638

Опубликована: Янв. 9, 2025

Dysregulation of RNA processing has in recent years emerged as a significant contributor to neurodegeneration. The diverse mechanisms and molecular functions underlying underscore the essential role regulation maintaining neuronal health function. molecules are bound by RNA-binding proteins (RBPs), interactions between RNAs RBPs commonly affected In this review, we highlight progress understanding dysregulated RNA-processing pathways causes RBP dysfunction across various neurodegenerative diseases. We discuss both established emerging RNA-mediated neuropathogenesis rapidly evolving field. Furthermore, explore development potential RNA-targeting therapeutic approaches for treatment

Язык: Английский

Процитировано

5

Nuclear speckles: dynamic hubs of gene expression regulation DOI Creative Commons
İbrahim Ilik, Tuğçe Aktaş

FEBS Journal, Год журнала: 2021, Номер 289(22), С. 7234 - 7245

Опубликована: Июль 10, 2021

Complex, multistep biochemical reactions that routinely take place in our cells require high concentrations of enzymes, substrates, and other structural components to proceed efficiently typically chemical environments can inhibit their immediate vicinity. Eukaryotic solve these problems by restricting such into diffusion‐restricted compartments within the cell called organelles be separated from environment a lipid membrane, or membrane‐less form through liquid–liquid phase separation (LLPS). One most easily noticeable earliest discovered organelle is nucleus, which harbors genetic material where transcription RNA polymerases produces messenger RNAs plethora noncoding RNAs, turn are required for translation mRNAs cytoplasm. The interior nucleus not uniform soup biomolecules rather consists variety bodies, as nucleolus, nuclear speckles (NS), paraspeckles, Cajal histone locus more. In this review, we will focus on NS with an emphasis recent developments including own findings about formation two large IDR‐rich proteins SON SRRM2.

Язык: Английский

Процитировано

89

SRRM2 organizes splicing condensates to regulate alternative splicing DOI
Shaohai Xu,

Soak-Kuan Lai,

Donald Yuhui Sim

и другие.

Nucleic Acids Research, Год журнала: 2022, Номер 50(15), С. 8599 - 8614

Опубликована: Авг. 5, 2022

Abstract SRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows organizes nuclear speckles along the cell cycle. As bona-fide splicing factor present spliceosome structures, deficiency induces skipping cassette exons short introns weak splice sites, tending to change large protein domains. In THP-1 myeloid-like depletion compromises viability, upregulates differentiation markers, sensitizes cells anti-leukemia drugs. FES isoform attenuates innate inflammatory responses, MUC1 isoforms undergo shedding oncogenic properties. We conclude acts as scaffold organize speckles, regulating alternative immunity homeostasis.

Язык: Английский

Процитировано

71

Nuclear speckles – a driving force in gene expression DOI Open Access

Gabriel P. Faber,

Shani Nadav-Eliyahu,

Yaron Shav‐Tal

и другие.

Journal of Cell Science, Год журнала: 2022, Номер 135(13)

Опубликована: Июль 1, 2022

Nuclear speckles are dynamic membraneless bodies located in the cell nucleus. They harbor RNAs and proteins, many of which splicing factors, that together display complex biophysical properties dictating nuclear speckle formation maintenance. Although these were discovered decades ago, only recently has in-depth genomic analysis begun to unravel their essential functions modulation gene activity. Major advancements mapping techniques combined with microscopy approaches have enabled insights into roles may play enhancing expression, how positioning specific landmarks can regulate expression RNA processing. Some studies drawn a link between disease. Certain maladies either involve directly or dictate localization reorganization factors. This is most striking during viral infection, as viruses alter entire architecture highjack host machinery. As discussed this Review, represent fascinating target study not reveal links positioning, genome subcompartments activity, but also potential for therapeutics.

Язык: Английский

Процитировано

69

Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation DOI Creative Commons
Romany Abskharon, M.R. Sawaya, David R. Boyer

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(15)

Опубликована: Апрель 4, 2022

In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms autopsied brains. Evidence suggests aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at level atomic structure. Here, we present 3.4-Å resolution structure fibrils full-length recombinant tau protein presence RNA, determined by electron cryomicroscopy (cryo-EM). The reveals familiar in-register cross-β amyloid scaffold but with a small fibril core spanning residues Glu391 to Ala426, region disordered fuzzy coat all previously studied polymorphs. is bound on surface positively charged Arg406 His407 runs parallel axis. dissolve when RNase added, showing necessary for integrity. While this cannot exist simultaneously structures extracted from patients’ brains, it could conceivably account nucleating effects cofactors followed remodeling as mature.

Язык: Английский

Процитировано

63

Tau interactome and RNA binding proteins in neurodegenerative diseases DOI Creative Commons
Tomas Kavanagh, Aditi Halder, Eleanor Drummond

и другие.

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Окт. 17, 2022

Pathological tau aggregation is a primary neuropathological feature of many neurodegenerative diseases. Intriguingly, despite the common presence aggregates in these diseases affected brain regions, clinical symptoms, and morphology, conformation, isoform ratio present varies widely. The tau-mediated disease mechanisms that drive are still unknown. Tau interactome studies critically important for understanding tauopathy. They reveal interacting partners define pathways, interactions provide potential insight into cellular environment protein during pathological aggregation. Here we combined analysis 12 human tissue, cell culture models rodent disease. Together, identified 2084 proteins interact with tissue 1152 Our revealed consistent enrichment between involved RNA binding, ribosome, proteasome function. Comparison substantial differences two species. We also performed second to identify enriched neurons containing granulovacuolar degeneration or neurofibrillary tangle pathology. These results timed dysregulation as pathology develops. binding proteins, particularly HNRNPs, emerged early disease-associated interactors therefore may have an role driving

Язык: Английский

Процитировано

62