Alternative splicing and related RNA binding proteins in human health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 2, 2024

Abstract Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications protein structure functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal spatial roles, thereby associating with standard biological activities diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role regulating alternative events. Under physiological the diversity of mediated by influences structure, function, interaction, localization proteins, participating differentiation development array tissues organs. pathological alterations are linked various diseases, particularly cancer. These changes can lead gene patterns, culminating loss For instance, cancer, abnormalities RBPs may result aberrant expression cancer-associated genes, promoting onset progression tumors. also associated numerous neurodegenerative diseases autoimmune Consequently, study across different holds significant value. review provides detailed account recent advancements tissue which aids deepening understanding complexity offers new insights methodologies for precision medicine.

Язык: Английский

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RNAi-based drug design: considerations and future directions

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(5), С. 341 - 364

Опубликована: Апрель 3, 2024

Язык: Английский

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Chemically Modified Platforms for Better RNA Therapeutics

Chemical Reviews, Год журнала: 2024, Номер 124(3), С. 929 - 1033

Опубликована: Янв. 29, 2024

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential disease prevention and treatment. However, despite their remarkable achievements, these encounter substantial challenges including low stability, susceptibility to degradation by nucleases, prominent negative charge, thereby hindering further development. Chemically modified platforms emerged as strategic innovation, focusing on precise alterations either RNA moieties or associated delivery vectors. This comprehensive review delves into platforms, underscoring significance augmenting performance translational prospects of therapeutics. It encompasses an in-depth analysis various chemically that been instrumental propelling therapeutics toward clinical utility. Moreover, scrutinizes rationale behind diverse chemical modification techniques aiming at optimizing therapeutic efficacy molecules, facilitating robust management. Recent empirical studies corroborating enhancement through modifications are highlighted. Conclusively, we offer profound insights transformative impact drugs delineates prospective trajectories for future development integration.

Язык: Английский

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RNA dysregulation in neurodegenerative diseases

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

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Targeting modulation of intestinal flora through oral route by an antimicrobial nucleic acid-loaded exosome-like nanovesicles to improve Parkinson’s disease

Science Bulletin, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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GFAP-isoforms in the nervous system: Understanding the need for diversity

Current Opinion in Cell Biology, Год журнала: 2024, Номер 87, С. 102340 - 102340

Опубликована: Фев. 23, 2024

Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) expressed in specific types of glial cells the nervous system. The expression GFAP highly regulated during brain development and neurological diseases. presence distinct GFAP-isoforms various cell types, developmental stages, diseases indicates that (post-)transcriptional regulation has a role physiology pathology. differ sub-cellular localisation, IF-network assembly properties, IF-dynamics which results molecular interactions mechanical properties IF-network. Therefore, likely mechanism by radial glia, astrocytes, glioma can modulate cellular function.

Язык: Английский

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Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Cell stem cell, Год журнала: 2024, Номер 31(8), С. 1162 - 1174.e8

Опубликована: Июнь 24, 2024

Aging is the biggest risk factor for development of Alzheimer's disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators neuronal age and show that neddylation pathway regulates both cellular AD neurodegeneration in human stem cell model. Specifically, demonstrate blocking increased hallmarks aging led an increase Tau aggregation phosphorylation neurons carrying APPswe/swe mutation. Aged but not isogenic control also showed progressive decrease viability. Selective loss upon inhibition was similarly observed other Parkinson's (PD) models, including PSENM146V/M146V cortical LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates can reveal late-onset phenotypes, identifies new potential targets modulate progression, describes strategy program age-associated phenotypes into models disease.

Язык: Английский

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Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome

Science, Год журнала: 2024, Номер 386(6721), С. 551 - 560

Опубликована: Окт. 31, 2024

The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 components and regulators human cancer cells reconstruction functional splicing factor networks govern different classes alternative decisions. results disentangle intricate circuits cross-regulation, reveal precise architecture late-assembling U4/U6.U5 tri-small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, discover an unprecedented division labor among protein U1 snRNP for regulating exon definition 5' selection. Thus, we provide resource explore physiological pathological mechanisms regulation.

Язык: Английский

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A systematic benchmark of Nanopore long-read RNA sequencing for transcript-level analysis in human cell lines

Nature Methods, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Abstract The human genome contains instructions to transcribe more than 200,000 RNAs. However, many RNA transcripts are generated from the same gene, resulting in alternative isoforms that highly similar and remain difficult quantify. To evaluate ability study transcript expression, we profiled seven cell lines with five different RNA-sequencing protocols, including short-read cDNA, Nanopore long-read direct RNA, amplification-free cDNA PCR-amplified sequencing, PacBio IsoSeq, multiple spike-in controls, additional transcriptome-wide N 6 -methyladenosine profiling data. We describe differences read length, coverage, throughput reporting sequencing robustly identifies major isoforms. illustrate value of SG-NEx data identify isoforms, novel transcripts, fusion modifications. Together, provide a comprehensive resource enabling development benchmarking computational methods for complex transcriptional events at isoform-level resolution.

Язык: Английский

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Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16259 - 16259

Опубликована: Ноя. 13, 2023

Alzheimer’s disease (AD) is a complex multifactorial disorder that poses substantial burden on patients, caregivers, and society. Considering the increased aging population life expectancy, incidence of AD will continue to rise in following decades. However, molecular pathogenesis remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, effective therapeutics halt or slow progression urgently needed. As powerful genetic regulators, microRNAs (miRNAs) receiving increasing attention due their implications initiation, development, theranostics various diseases, including AD. In this review, we summarize miRNAs directly target microtubule-associated protein tau (MAPT), amyloid precursor (APP), β-site APP-cleaving enzyme 1 (BACE1) transcripts regulate alternative splicing APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent 5 (CDK5), death-associated (DAPK1), well apolipoprotein E, targeted by control phosphorylation amyloidogenic APP processing leading Aβ pathologies. Moreover, there evidence miRNA-mediated modulation inflammation. Furthermore, circulating serum plasma patients noninvasive biomarkers with diagnostic potential reviewed. addition, miRNA-based optimized nanocarriers exosomes options treatment discussed.

Язык: Английский

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