scholarly journals DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM

2021 ◽  
Author(s):  
D Beijer ◽  
HJ Kim ◽  
L Guo ◽  
K O’Donovan ◽  
I Mademan ◽  
...  
Keyword(s):  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Motor Neuropathy ◽  
Hnrnp A1 ◽  
Hereditary Motor Neuropathy ◽  
Critical Components ◽  
Spectrum Of Patients

ABSTRACTMutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form ribonucleoproteins. hnRNPs are a major subclass of evolutionarily conserved RBPs that are primarily concentrated in the nucleus and are heavily involved in pre-mRNA splicing, mRNA stability and transcriptional/translational regulation. During times of stress, standard translational programming is interrupted, and hnRNPs, mRNA, and other RBPs condense in the cytoplasm, forming liquid-liquid phase separated (LLPS) membraneless organelles termed stress granules (SGs). SGs are central to the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). hnRNPs and other RBPs are critical components of SGs. Indeed, the link between SGs, hnRNPs, and neurodegenerative diseases has been established by the identification of additional mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, each of which can directly lead to ALS, IBM and other related neurodegenerative diseases. Here, we report and characterize four novel HNRNPA1 mutations and two known HNRNPA1 mutations, previously reported as being causal for ALS, in a broad spectrum of patients with hereditary motor neuropathy (HMN), ALS, and myopathy. Our results show the different effects of mutations on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics, indicating the possibility of different underlying pathomechanisms for HNRNPA1 mutations with a possible link to the clinical phenotypes.

RNA-Binding Proteins and Translation in Neurodegenerative Disease

2020 ◽  
Author(s):  
Kent E. Duncan
Keyword(s):  
Neurodegenerative Diseases ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Potential Contribution ◽  
Fused In Sarcoma ◽  
Specific Mrnas ◽  
Ataxia Syndrome ◽  
Research Frontiers

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

hnRNP A1 Selectively Interacts Through its Gly-rich Domain with Different RNA-binding Proteins

1996 ◽  
Vol 259 (3) ◽  
pp. 337-348 ◽  
Author(s):  
Luca Cartegni ◽  
Mariacaterina Maconi ◽  
Elena Morandi ◽  
Fabio Cobianchi ◽  
Silvano Riva ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Hnrnp A1 ◽  
Rich Domain

scholarly journals TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression

2019 ◽  
Author(s):  
Josiah J. Herzog ◽  
Mugdha Deshpande ◽  
Weijin Xu ◽  
Reazur Rahman ◽  
Hannah Suib ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Dendritic Morphology ◽  
New Approach ◽  
Creb Activation ◽  
Dendritic Branching ◽  
Transcriptional Output ◽  
Dendritic Complexity ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative diseases that present with similar TDP-43 pathology in patient tissue. TDP-43 is an RNA-binding protein and forms aggregates in neurons of ALS and FTD patients as well as in a subset of patients diagnosed with other neurodegenerative diseases. Despite our understanding that TDP-43 is essential for many aspects of RNA metabolism, it remains obscure how TDP-43 dysfunction contributes to neurodegeneration. Interestingly, several neurological disorders display altered dendritic morphology and complexity, which are thought to precede neurodegeneration. In this study, we used TRIBE (targets of RNA-binding proteins identified by editing) as a new approach to identify signaling pathways that regulate dendritic branching downstream of TDP-43. We found that TDP-43 targets are enriched for pathways that signal to the CREB transcription factor. We further found that TDP-43 dysfunction inhibits CREB activation and CREB transcriptional output, and restoring CREB signaling rescued defects in dendritic branching. Our data therefore provide a novel mechanism by which TDP-43 dysfunction interferes with dendritic branching, and define new pathways for therapeutic intervention in neurodegenerative diseases.

scholarly journals Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1475
Author(s):  
Veronica Ruta ◽  
Vittoria Pagliarini ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Rna Processing ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Signal Transduction Pathways ◽  
Challenges And Opportunities ◽  
Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

Coordinate regulation of heterogeneous nuclear ribonucleoprotein dynamics by steroid hormones in the human fallopian tube and endometrium in vivo and in vitro

2012 ◽  
Vol 302 (10) ◽  
pp. E1269-E1282 ◽  
Author(s):  
Ruijin Shao ◽  
Xiaoqin Wang ◽  
Birgitta Weijdegård ◽  
Anders Norström ◽  
Julia Fernandez-Rodriguez ◽  
...  
Keyword(s):  
Steroid Hormones ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intracellular Localization ◽  
Hnrnp A1 ◽  
Fallopian Tubes ◽  
Protein Levels ◽  
Human Fallopian Tube

Heterogeneous nuclear ribonucleoproteins (hnRNPs), which are chromatin-associated RNA-binding proteins, participate in mRNA stability, transport, intracellular localization, and translation by acting as transacting factors. Several studies have shown that steroid hormones can regulate hnRNP expression. However, to date, the regulation of hnRNPs and their interactions with steroid hormone signaling in fallopian tubes and endometrium are not fully elucidated. In the present study, we determined whether hnRNP expression is regulated during the menstrual cycle and correlates with estrogen receptor (ER) and progesterone receptor (PR) levels in human fallopian tubes in vivo. Because of the limited availability of human tubal tissues for the research, we also explored the mechanisms of hnRNP regulation in human endometrium in vitro. Fallopian tissue was obtained from patients in the early, late, and postovulatory phases and the midsecretory phase and endometrial tissue from premenopausal and postmenopausal women undergoing hysterectomy. We measured expression of hnRNPs and assessed their intracellular localization and interactions with ERs and PRs. We also determined the effects of human chorionic gonadotropin, 17β-estradiol (E2), and progesterone (P4) on hnRNP expression. In fallopian tubes, mRNA and protein levels of hnRNP A1, AB, D, G, H, and U changed dynamically during ovulation and in the midsecretory phase. In coimmunolocation and coimmunoprecipitation experiments, hnRNPs interacted with each other and with ERs and PRs in fallopian tubes. After treatment with E2 and/or P4 to activate ERs and PRs, hnRNP A1, AB, D, G, and U proteins displayed overlapping but distinct patterns of regulation in the endometrium in vitro. Our findings expand the physiological repertoire of hnRNPs in human fallopian tubes and endometrium and suggest that steroid hormones regulate different hnRNPs directly by interacting with ERs and/or PRs or indirectly by binding other hnRNPs. Both actions may contribute to regulation of gene transcription.

scholarly journals A nuclear localization domain in the hnRNP A1 protein.

1995 ◽  
Vol 129 (3) ◽  
pp. 551-560 ◽  
Author(s):  
H Siomi ◽  
G Dreyfuss
Keyword(s):  
Nuclear Localization ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Motif ◽  
Hnrnp A1 ◽  
Binding Domains ◽  
Rich Domain ◽  
Localization Domain ◽  
Hnrnp Proteins

The heterogeneous nuclear RNP (hnRNP) A1 protein is one of the major pre-mRNA/mRNA binding proteins in eukaryotic cells and one of the most abundant proteins in the nucleus. It is localized to the nucleoplasm and it also shuttles between the nucleus and the cytoplasm. The amino acid sequence of A1 contains two RNP motif RNA-binding domains (RBDs) at the amino terminus and a glycine-rich domain at the carboxyl terminus. This configuration, designated 2x RBD-Gly, is representative of perhaps the largest family of hnRNP proteins. Unlike most nuclear proteins characterized so far, A1 (and most 2x RBD-Gly proteins) does not contain a recognizable nuclear localization signal (NLS). We have found that a segment of ca. 40 amino acids near the carboxyl end of the protein (designated M9) is necessary and sufficient for nuclear localization; attaching this segment to the bacterial protein beta-galactosidase or to pyruvate kinase completely localized these otherwise cytoplasmic proteins to the nucleus. The RBDs and another RNA binding motif found in the glycine-rich domain, the RGG box, are not required for A1 nuclear localization. M9 is a novel type of nuclear localization domain as it does not contain sequences similar to classical basic-type NLS. Interestingly, sequences similar to M9 are found in other nuclear RNA-binding proteins including hnRNP A2.

Functional diversity of the hnRNPs: past, present and perspectives

2010 ◽  
Vol 430 (3) ◽  
pp. 379-392 ◽  
Author(s):  
Siew Ping Han ◽  
Yue Hang Tang ◽  
Ross Smith
Keyword(s):  
Translational Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Functional Divergence ◽  
Nucleic Acid Metabolism ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Nascent Transcripts

The hnRNPs (heterogeneous nuclear ribonucleoproteins) are RNA-binding proteins with important roles in multiple aspects of nucleic acid metabolism, including the packaging of nascent transcripts, alternative splicing and translational regulation. Although they share some general characteristics, they vary greatly in terms of their domain composition and functional properties. Although the traditional grouping of the hnRNPs as a collection of proteins provided a practical framework, which has guided much of the research on them, this approach is becoming increasingly incompatible with current knowledge about their structural and functional divergence. Hence, we review the current literature to examine hnRNP diversity, and discuss how this impacts upon approaches to the classification of RNA-binding proteins in general.

scholarly journals An interaction network of RNA-binding proteins involved in Drosophila oogenesis

2020 ◽  
Author(s):  
Prashali Bansal ◽  
Johannes Madlung ◽  
Kristina Schaaf ◽  
Boris Macek ◽  
Fulvia Bono
Keyword(s):  
Translational Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Direct Interaction ◽  
Interaction Network ◽  
Splicing Factors ◽  
Mrna Regulation ◽  
Interaction Partners ◽  
Maternal Transcripts

AbstractDuring Drosophila oogenesis, the localization and translational regulation of maternal transcripts relies on RNA-binding proteins (RBPs). Many of these RBPs localize several mRNAs and may have additional direct interaction partners to regulate their functions. Using immunoprecipitation from whole Drosophila ovaries coupled to mass spectrometry, we examined protein-protein associations of 6 GFP-tagged RBPs expressed at physiological levels. Analysis of the interaction network and further validation in human cells allowed us to identify 26 previously unknown associations, besides recovering several well characterized interactions. We identified interactions between RBPs and several splicing factors, providing links between nuclear and cytoplasmic events of mRNA regulation. Additionally, components of the translational and RNA decay machineries were selectively co-purified with some baits, suggesting a mechanism for how RBPs may regulate maternal transcripts. Given the evolutionary conservation of the studied RBPs, the interaction network presented here provides the foundation for future functional and structural studies of mRNA localization across metazoans.

scholarly journals Programmable mammalian translational modulators by CRISPR-associated proteins

2021 ◽  
Author(s):  
Shunsuke Kawasaki ◽  
Hiroki Ono ◽  
Moe Hirosawa ◽  
Takeru Kuwabara ◽  
Hirohide Saito
Keyword(s):  
Mammalian Cells ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Circuits ◽  
Genomic Engineering ◽  
Associated Proteins ◽  
Translational Regulators ◽  
Rna Motif ◽  
Cas Proteins

The complexity of synthetic genetic circuits relies on repertories of biological circuitry with high orthogonality. Although post-transcriptional circuitry relying on RNA-binding proteins (RBPs) qualifies as a repertory, the limited pool of regulatory devices hinders network modularity and scalability. Here we propose CaRTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Genomic Engineering) to repurpose CRISPR-associated (Cas) proteins as translational modulators. We demonstrate that a set of Cas proteins are able to repress (OFF) or activate (ON) the translation of mRNAs that contain a Cas-binding RNA motif in the 5'-UTR. We designed 81 different types of translation OFF and ON switches and verified their functional characteristics. Many of them functioned as efficient translational regulators and showed orthogonality in mammalian cells. By interconnecting these switches, we designed and built artificial circuits, including 60 translational AND gates. Moreover, we show that various CRISPR-related technologies, including anti-CRISPR and split-Cas9 platforms, can be repurposed to control translation. Our Cas-mediated translational regulation is compatible with transcriptional regulation by Cas proteins and increases the complexity of synthetic circuits with fewer elements. CaRTRIDGE builds protein-responsive mRNA switches more than ever and leads to the development of both Cas-mediated genome editing and translational regulation technologies.

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