The lncRNAMalat1is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons

Genes & Development, Journal Year: 2024, Volume and Issue: 38(7-8), P. 294 - 307

Published: April 1, 2024

Synaptic function in neurons is modulated by local translation of mRNAs that are transported to distal portions axons and dendrites. The metastasis‐associated lung adenocarcinoma transcript 1 ( MALAT1 ) broadly expressed across cell types, almost exclusively as a nuclear long noncoding RNA. We found differentiating neurons, portion Malat1 RNA redistributes the cytoplasm. Depletion using antisense oligonucleotides (ASOs) stimulates expression particular pre- postsynaptic proteins, implicating their regulation. Neuronal localized puncta both dendrites costain with Staufen1 protein, similar neuronal granules formed locally translated mRNAs. Ribosome profiling cultured mouse cortical identified ribosome footprints within 5′ region containing short open reading frames. upstream-most frame (M1) locus was linked GFP-coding sequence embryonic stem cells. When these gene-edited cells were differentiated into glutamatergic M1-GFP fusion protein expressed. Antibody staining for M1 peptide confirmed its presence wild-type showed enhanced synaptic stimulation KCl. Our results indicate serves cytoplasmic coding brain modulates function.

Language: Английский

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Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD

Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 15, 2025

Abstract Background Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity learning/memory development. The trafficking mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into spines upon glutamate-induced receptor activation. However, molecular mechanism(s) behind spine entry under metabotropic glutamate (mGluR)-mediated neuroactivation long-term depression (LTD) as well fate these inside still elusive. Method Different imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence situ hybridization (FISH), live cell imaging, tracking using beacon, mouse model study used to elucidate a novel mechanism regulating mammalian neurons. Results We demonstrate here that brief mGluR1 activation-mediated dephosphorylation pFMRP (S499) results dissociation FMRP from TDP-43 handover TDP-43/ Rac1 mRNA complex track on microtubules myosin V actin filaments. thus enters translational reactivation increases mature density. In contrast, during mGluR1-mediated neuronal LTD, phosphorylated complex, being associated with kinesin 1-FMRP/cortactin/drebrin, owing Ca 2+ -dependent microtubule invasion spines, but without reactivation. VPA-ASD model, this regulation become anomalous. Conclusions This study, first time, highlights importance posttranslational modification RBPs, such neurodevelopmental disease-related protein FMRP, switch dendrite-to-spine specific neurotransmissions. misregulation could contribute pathogenesis FMRP-related neurodisorders including autism spectrum disorder (ASD). It also indicate connection between ASD neurodegenerative opens up new perspective research proteinopathy among patients ASD.

Language: Английский

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Axonal RNA localization is essential for long-term memory

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 15, 2025

Abstract Localization of mRNAs to neuronal terminals, coupled local translation, has emerged as a prevalent mechanism controlling the synaptic proteome. However, physiological regulation and function this process in context mature vivo memory circuits remained unclear. Here, we combined synaptosome RNA profiling with whole brain high-resolution imaging uncover different localization patterns axons Drosophila Mushroom Body neurons, some exhibiting regionalized, input-dependent, recruitment along axons. By integrating transcriptome-wide binding approaches functional assays, show that conserved Imp protein controls transport characterize mutant which is selectively impaired. Using unique mutant, demonstrate axonal mRNA required for long-term, but not short-term, behavioral memory. This work uncovers circuit-dependent targeting demonstrates importance consolidation.

Language: Английский

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Mechanistic insights into the basis of widespread RNA localization

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(7), P. 1037 - 1046

Published: July 1, 2024

Language: Английский

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Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 18, 2024

Abstract Once considered unconventional cellular structures, membraneless organelles (MLOs), substructures involved in biological processes or pathways under physiological conditions, have emerged as central players dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, metabolism to cancer, influence on human health disease extends widely. This review discusses underlying mechanisms LLPS, biophysical properties that drive MLO formation, their implications for We highlight recent advances understanding how physicochemical environment, molecular interactions, post-translational modifications regulate LLPS dynamics. offers an overview discovery current biomolecular condensate conditions diseases. article aims deliver latest insights by analyzing research, highlighting critical role organization. The discussion also covers membrane-associated condensates cell signaling, including those involving T-cell receptors, stress granules linked lysosomes, within Golgi apparatus. Additionally, potential targeting clinical settings is explored, promising avenues future research therapeutic interventions.

Language: Английский

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How energy determines spatial localisation and copy number of molecules in neurons

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 6, 2025

Abstract In neurons, the quantities of mRNAs and proteins are traditionally assumed to be determined by functional, electrical or genetic factors. Yet, there may also global, currently unknown computational rules that valid across different molecular species inside a cell. Surprisingly, our results show energy for turnover is significant cellular expense, en par with spiking cost, which requires energy-saving strategies. We drive save determines transcript their location while acting differently on each depending length, longevity other features respective molecule. combined own data experimental reports from five large-scale mRNA proteomics screens, comprising more than ten thousand reveal underlying principles localisation. found minimisation explain experimentally-reported exponential rank distributions protein copy numbers. Our further robust benefits when certain classes moved into dendrites, example long amino acid chains large non-coding regions half-lives proving surprising insights at level populations.

Language: Английский

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Deciphering Phase-Separated Mitochondrial RNA Granules under Stress Conditions with the Mitoribosome-Targeting Small Molecule

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

RNA granules are liquid-liquid-phase-separated condensates comprising and proteins. Despite growing insights into their biological functions, studies have predominantly relied on methodologies lacking adequate chemical tools. Here, we introduce ICP-CHARGINGS, a concept for efficiently identifying probes to characterize of interest among nucleic acid-targeting agents. Focusing mitochondrial (MRGs), whose functions remain elusive, developed methodology within this framework identified NATA, new fluorescent molecule that, following mechanistic studies, was found bind the mitoribosome, enabling MRG labeling recognition. Using NATA reveal potential buffering roles MRGs, demonstrated close correlation between maintenance assembly cellular survival proliferation under cold shock hypoxic stress. Overall, introduction implementation ICP-CHARGINGS strategy provide specialized tool advancing our comprehension biology establish paradigm elucidating structures that can be targeted by small molecules, paving way developing tailored diverse in future research.

Language: Английский

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Attenuating the neuronal response to chronic stress through transcription factor aggregation

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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RNA guanine content and G-quadruplex structure tune the phase behavior and material properties of biomolecular condensates

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 18, 2025

RNA binding proteins (RBPs) are enriched in phase separated biomolecular assemblies across cell types. These RBPs often harbor arginine-glycine rich RGG motifs, which can drive separation, and preferentially interact with G-quadruplex (G4) structures, particularly the neuron. Increasing evidence underscores important role that sequence structure play contributing to form function of protein condensates, however, less is known about G4 RNAs their interaction domains specifically. In this study we focused on model protein, Fragile X mental retardation (FMRP), investigate how G4-containing sequences impact behavior material properties condensates. FMRP implicated development Syndrome, neuronal granules where it thought aid mRNA trafficking translational control. Here, examined increasing G content propensity complex RGG-containing low complexity region (LCR) FMRP. We found, while triggers aggregation poly-arginine, all supported separation into liquid droplets FMRP-LCR. Combining microrheology, fluorescence recovery after photobleaching, measured a moderate increase viscosity decrease dynamics for G-content, detected no measurable elasticity as structure. Additionally, found methylation decreased affinity, modification did not condensate suggesting sequence/structure greater than affinity determining emergent Together, work lends much needed insight ways G-rich tune assembly, protein/RNA condensates and/or granules.

Language: Английский

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Expanding toolkit for RNP granule transcriptomics

Polymer Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Language: Английский

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