Localized translation and sarcomere maintenance requires ribosomal protein SA in mice DOI Creative Commons
Rami J. Haddad, Omer Sadeh, Tamar Ziv

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Май 14, 2024

Cardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and significance of translation are unknown. Using proximity labeling, we identified Ribosomal Protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, loss RPSA led to impaired local protein reduced sarcomere integrity. By employing CAS9 expressing mice along with adeno-associated viruses CRE recombinase single-guide RNAs targeting Rpsa, knocked out Rpsa in vivo observed mis-localization ribosomes diminished translation. These genetic mosaic knockout subset cardiomyocytes developed dilated cardiomyopathy, featuring atrophy RPSA-deficient compensatory hypertrophy unaffected left ventricular dilation, contractile function. We demonstrate that C-terminal domain is sufficient Z-lines if microtubule network disrupted loses its sarcomeric localization. findings highlight ribosomal factor essential ribosome Z-line, facilitating maintenance.

Язык: Английский

Neuronal maturation and axon regeneration: unfixing circuitry to enable repair DOI
Brett J. Hilton, Jarred M. Griffin, James W. Fawcett

и другие.

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(10), С. 649 - 667

Опубликована: Авг. 20, 2024

Язык: Английский

Процитировано

18
Mechanisms of axonal support by oligodendrocyte-derived extracellular vesicles DOI
Eva‐Maria Krämer‐Albers, Hauke Werner

Nature reviews. Neuroscience, Год журнала: 2023, Номер 24(8), С. 474 - 486

Опубликована: Май 31, 2023

Язык: Английский

Процитировано

27
Axonal RNA localization is essential for long-term memory DOI Creative Commons
Bruna R. de Queiroz,

Hiba Laghrissi,

S. Rajeev

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 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.

Язык: Английский

Процитировано

1
Disrupting pathologic phase transitions in neurodegeneration DOI Creative Commons

Bryan Hurtle,

Longxin Xie, Christopher J. Donnelly

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(13)

Опубликована: Июль 2, 2023

Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble accumulations the resulting deficits neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer's disease, Parkinson's frontotemporal lobar degeneration, amyotrophic lateral sclerosis, exhibit unique disease-specific biochemical signatures abnormal depositions that often correlate with disease pathogenesis. Recent evidence indicates many pathologic proteins assemble into liquid-like phases through highly coordinated process of liquid-liquid phase separation. Over last decade, biomolecular transitions emerged as fundamental mechanism cellular organization. Liquid-like condensates organize functionally related biomolecules within cell, neuropathology-associated reside these dynamic structures. Thus, examining enhances our understanding molecular mechanisms mediating toxicity across diseases. This Review explores known contributing to aberrant focusing on tau TDP-43 proteinopathies outlining potential therapeutic strategies regulate events.

Язык: Английский

Процитировано

22
Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis DOI Open Access
Vasiliy Reshetnikov, Ilya M. Terenin, Galina Shepelkova

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 888 - 888

Опубликована: Янв. 10, 2024

mRNA vaccines have been shown to be effective in combating the COVID-19 pandemic. The amount of research on use mRNAs as preventive and therapeutic modalities has undergone explosive growth last few years. Nonetheless, issue stability molecules their translation efficiency remains incompletely resolved. These characteristics directly affect expression level a desired protein. Regulatory elements RNA—5′ 3′ untranslated regions (UTRs)—are responsible for efficiency. An optimal combination regulatory sequences allows significantly increase target protein’s expression. We assessed encoding firefly luciferase with various 5′ 3′UTRs vitro cell lines DC2.4 THP1. found that containing 5′UTR from eukaryotic genes HBB, HSPA1A, Rabb, or H4C2, adenoviral leader sequence TPL, resulted higher levels bioluminescence 4 h after transfection cells compared used mRNA-1273 BNT162b2 Moderna BioNTech. TPL also showed (as Moderna) at generating T-cell response mice immunized multiepitope antigen. By contrast, no effects 5′UTRs were detectable THP1 cells, suggesting observed are type specific. Further analyses enabled us identify potential type-specific RNA-binding proteins differ landing sites within 3′UTRs. Taken together, our data indicate high 5′UTR, according experiments C57BL/6 mice.

Язык: Английский

Процитировано

8
Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications DOI Creative Commons
Yingying Shi,

Miaoyuan Shi,

Yì Wáng

и другие.

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

Опубликована: Ноя. 14, 2024

Abstract In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge can be largely attributed to demonstration of distinct advantages offered by various mRNA molecules, alongside rapid advancements nucleic delivery systems. It is noteworthy that immunogenicity presents a double-edged sword. context immunotherapy, extra supplementation adjuvant generally required for induction robust immune responses. Conversely, non-immunotherapeutic scenarios, activation unwanted considering host tolerability high expression demand mRNA-encoded functional proteins. Herein, mainly focused on linear non-replicating mRNA, we overview preclinical clinical progress prospects medicines encompassing vaccines other therapeutics. We also highlight importance focusing host-specific variations, including age, gender, pathological condition, concurrent medication individual patient, maximized efficacy safety upon administration. Furthermore, deliberate potential challenges may encounter realm disease treatment, current endeavors improvement, as well application future advancements. Overall, this review aims present comprehensive understanding mRNA-based therapies while illuminating prospective development drugs.

Язык: Английский

Процитировано

7
Calibrated ribosome profiling assesses the dynamics of ribosomal flux on transcripts DOI Creative Commons
Kotaro Tomuro, Mari Mito, Hirotaka Toh

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 26, 2024

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism protein synthesis. However, current method substantial issues: contamination by rRNAs and lack appropriate methods to measure numbers in transcripts. Here, we overcome these hurdles through development "Ribo-FilterOut", separation footprints from subunits ultrafiltration, "Ribo-Calibration", relies external spike-ins stoichiometrically defined mRNA-ribosome complexes. A combination approaches estimates number ribosomes transcript, translation initiation rate, overall events before its decay, all genome-wide manner. Moreover, our reveals allocation under heat shock stress, during aging, across cell types. Our strategy modified profiling measures kinetic stoichiometric parameters cellular transcriptome. faces issues with rRNA measurements authors develop Ribo-FilterOut Ribo-Calibration, can be used estimate various conditions.

Язык: Английский

Процитировано

6
Buffering of genetic dominance by allele-specific protein complex assembly DOI Creative Commons
Mihaly Badonyi, Joseph A. Marsh

Science Advances, Год журнала: 2023, Номер 9(22)

Опубликована: Май 31, 2023

Protein complex assembly often occurs while subunits are being translated, resulting in complexes whose were translated from the same mRNA an allele-specific manner. It has thus been hypothesized that such cotranslational may counter assembly-mediated dominant-negative effect, whereby co-assembly of mutant and wild-type "poisons" activity. Here, we show cotranslationally assembling much less likely to be associated with autosomal dominant relative recessive disorders, disease mutations significantly depleted compared those loss-of-function mutations. We also find known effects tend expose their interfaces late during translation, lessening likelihood assembly. Finally, by combining properties other features, trained a computational model for predicting proteins non-loss-of-function mechanisms, which believe will considerable utility protein variant interpretation.

Язык: Английский

Процитировано

15
Regulation and function of poised mRNAs in lymphocytes DOI Creative Commons
Martin Turner

BioEssays, Год журнала: 2023, Номер 45(5)

Опубликована: Апрель 3, 2023

Abstract Pre‐existing but untranslated or ‘poised’ mRNA exists as a means to rapidly induce the production of specific proteins in response stimuli and safeguard limit actions these proteins. The translation poised enables immune cells express quickly genes that enhance responses. molecular mechanisms repress and, upon stimulation, enable have yet be elucidated. They likely reflect intrinsic properties mRNAs their interactions with trans‐acting factors direct away from into ribosome. Here, I discuss by which this might regulated.

Язык: Английский

Процитировано

14
Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation DOI Creative Commons
Jian-Xin Lin, Meili Ge, Chengyu Liu

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 27, 2024

Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal critical STAT5A STAT5B; however, the importance in vivo has not been assessed. Here we generate Stat5a Stat5b tyrosine-to-phenylalanine mutant knockin mice find they have greatly reduced CD8

Язык: Английский

Процитировано

4