Paraspeckle

Parkinson's disease (PD) is one of the complex neurodegenerative disorders, primarily characterized by motor deficits, including bradykinesia, tremor, rigidity, and postural instability. The underlying pathophysiology involves the progressive loss of dopaminergic neurons within the substantia nigra pars compacta, leading to dopamine depletion in the basal ganglia circuitry. While motor symptoms are hallmark features of PD, emerging research highlights a wide range of non-motor symptoms, including cognitive impairments, mood disturbances, and autonomic dysfunctions...

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2 -mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 ( PSPC1 ), as an additional synthetic lethal partner with BRCA1/2 , to enhance olaparib sensitivity in preclinical models of BRCA1/2 -mutated breast and ovarian cancers...

Cancer is a complicated illness that spreads indefinitely owing to epigenetic, genetic, and genomic alterations. Cancer cell multidrug susceptibility represents a severe barrier in cancer therapy. As a result, creating effective therapies requires a better knowledge of the mechanisms driving cancer development, progress, and resistance to medications. The human genome is predominantly made up of long non coding RNAs (lncRNAs), which are currently identified as critical moderators in a variety of biological functions...

Demixing of proteins and nucleic acids into condensed liquid phases is rapidly emerging as a ubiquitous mechanism underlying the complex spatiotemporal organisation of molecules within the cell. Long disordered regions of low sequence complexity (LCRs) are a common feature of proteins that form liquid-like microscopic biomolecular condensates. In particular, RNA-binding proteins with prion-like regions have emerged as key drivers of liquid demixing to form condensates such as nucleoli, paraspeckles and stress granules...

Many membraneless organelles (MLOs) formed through phase separation play crucial roles in various cellular processes. Although these MLOs co-exist in cells, how they maintain their independence without coalescence or engulfment remains largely unknown. Here, we investigated the molecular mechanism by which paraspeckles with core-shell architecture scaffolded by NEAT1_2 long noncoding RNAs exist as distinct MLOs. We identified NEAT1 deletion mutants that assemble paraspeckles that are incorporated into nuclear speckles...

Recent functional research on long noncoding RNAs (lncRNAs) has revealed their significant regulatory roles in gene expression and intracellular architecture. Well-characterized examples of such lncRNAs include Xist and NEAT1_2, which play critical roles in heterochromatin formation of inactive X-chromosomes and paraspeckle assembly, in mammalian cells. Both lncRNAs possess modular domain structures with multiple functionally distinct domains that serve as platforms for specific RNA-binding proteins (RBPs), which dictate the function of each lncRNA...

Fibrosis is the excess deposition of extracellular matrix involved in the pathogenesis of chronic diseases and finally leads to the disruption of tissue architecture and failure of organ function. Long noncoding RNAs (lncRNAs) are a class of RNAs with lengths greater than 200 nucleotides and do not code proteins, which regulate gene expression at multiple levels. Nuclear-enriched abundant transcript 1 (NEAT1) is a long noncoding RNA that is widely expressed in mammalian cells and known as essential architectural scaffold for the formation of paraspeckles...

Somatic mutations in the ASXL1 gene are commonly observed in myeloid neoplasms. Pathogenic ASXL1 mutations induce the expression of C-terminally truncated mutant ASXL1 protein. We have shown that wild-type ASXL1 is a phase-separating protein involved in the formation of paraspeckles, one of the best known membraneless organelles (MLOs). Mutant ASXL1 lacks the intrinsically disordered region, which is important for phase separation and fails to support paraspeckle formation. Additionally, paraspeckles are disrupted in hematopoietic cells derived from ASXL1-MT knockin mice...

Inflammatory cytokines that are secreted into the spinal trigeminal nucleus caudalis (Sp5C) may augment inflammation and cause pain associated with temporomandibular joint disorders (TMD). In a two-step process, we attached triphenylphosphonium (TPP) to the surface of a cubic liposome metal-organic framework (MOF) loaded with ruthenium (Ru) nanozyme. The design targeted mitochondria and was designated Mito-Ru MOF. This structure scavenges free radicals and reactive oxygen species (ROS) and alleviates oxidative stress...

Alzheimer's disease (AD) is the most common type of dementia and is a serious social and medical problem threatening human health. The present study investigated the effect and underlying action mechanism of triptolide (Tri) on AD progression. Reverse transcription-quantitative PCR and western blotting analysis were used to determine the changes in RNA expression and levels of NF-κB signaling pathway proteins before and after lipopolysaccharide (LPS) induction. Nucleocytoplasmic separation experiments determined the intracellular localization of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1)...

Long non-coding-RNAs (lncRNAs) are an expanding set of cis-/trans-regulatory RNA genes that outnumber the protein-coding genes. Although being increasingly discovered, the functional role of the majority of lncRNAs in diverse biological conditions is undefined. Increasing evidence supports the critical role of lncRNAs in the emergence, regulation, and progression of various viral infections including influenza, hepatitis, coronavirus, and human immunodeficiency virus. Hence, the identification of signature lncRNAs would facilitate focused analysis of their functional roles accounting for their targets and regulatory mechanisms associated with infections...

Paraspeckles (PS) are nuclear structures scaffolded by the long noncoding RNA NEAT1 and protein components such as NONO and SFPQ. We previously found that the upregulation of RNA N6-methyl-adenosine (m6 A) demethylase ALKBH5 facilitates hypoxia-induced paraspeckle assembly through erasing m6 A marks on NEAT1, thus stabilizing it. However, it remains unclear how these processes are spatiotemporally coordinated. Here we discover that ALKBH5 specifically binds to proteins in PS and forms phase-separated droplets that are incorporated into PS through its C-terminal intrinsically disordered region (cIDR)...

We investigated the role of miR-150-5p in osteoarthritic (OA) chondrocytes, as well as the possible regulatory role of long non-coding RNAs (lncRNAs) in miR-150-5p expression. TargetScan, StarBase, DIANA-LncBase, and Open Targets databases were used to predict miR-150-5p target genes, lncRNAs/miR-150-5p interactions, and OA-related genes. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Gene ontology (GO) and pathway analysis were performed using Enrichr database...

Phase-separated membraneless organelles often contain RNAs that exhibit unusual semi-extractability using the conventional RNA extraction method, and can be efficiently retrieved by needle shearing or heating during RNA extraction. Semi-extractable RNAs are promising resources for understanding RNA-centric phase separation. However, limited assessments have been performed to systematically identify and characterize semi-extractable RNAs. In this study, 1074 semi-extractable RNAs, including ASAP1, DANT2, EXT1, FTX, IGF1R, LIMS1, NEAT1, PHF21A, PVT1, SCMH1, STRG...

The early events of HIV-1 infection involve the transport of the viral core into the nucleus. This event triggers the translocation of CPSF6 from paraspeckles into nuclear speckles forming puncta-like structures. Our investigations revealed that neither HIV-1 integration nor reverse transcription is required for the formation of puncta-like structures. Moreover, HIV-1 viruses without viral genome are competent for the induction of CPSF6 puncta-like structures. In agreement with the notion that HIV-1 induced CPSF6 puncta-like structures are biomolecular condensates, we showed that osmotic stress and 1,6-hexanediol induced the disassembly of CPSF6 condensates...

PURPOSE: Parkinson's disease (PD) is the second most frequent neurodegenerative disease. The aim of our study is to explore the role and the regulatory mechanism of long noncoding RNA (lncRNA) NEAT1 in MPP+ -induced pyroptosis in a cell model of PD. MATERIALS AND METHODS: MPP+ -treated SH-SY5Y cells were used as an in vitro model of dopaminergic neurons for PD. Expression levels of miR-5047 and YAF2 mRNA were determined through qRT-PCR. TUNEL staining was carried out to analyze neuronal apoptosis...

N6-methyladenosine (m6 A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6 A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6 A demethylation activity of ALKBH5 by increasing its recognition of m6 A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6 A mRNA by ALKBH5, thereby promoting m6 A erasure...

The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus...

Human pregnane X receptor (PXR) is a major nuclear receptor that upregulates the expression of drug-metabolizing enzymes such as CYP3A4. In our recent study, it was revealed that PXR interacts with DAZ-associated protein 1 (DAZAP1), which is an essential component of the paraspeckle, a membraneless nuclear body, and the interaction was disassociated by rifampicin, a ligand of PXR. The purpose of this study was to clarify the roles of paraspeckles in PXR-mediated transcriptional regulation. Immunoprecipitation assays using PXR-overexpressing HepG2 (ShP51) cells revealed that PXR interacts with not only DAZAP1 but also NEAT1_2, a long noncoding RNA included in the paraspeckle, and that the interaction between PXR and NEAT1_2 was disassociated by rifampicin...

Increasing evidence has uncovered the essential roles of long noncoding RNAs (lncRNAs) in biological and pathological functions of dendritic cells (DCs) among patients with systemic lupus erythematosus (SLE). However, whether lncRNA nuclear paraspeckle assembly transcript 1 ( NEAT1 ) could modulate DCs, especially in the inflammation of SLE, remains largely unknown. Fifteen SLE patients and fifteen age-matched healthy controls were included, and their monocyte-derived dendritic cells (moDCs) were cultured in vitro...