Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1

Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNAs, containing inverted repeat (IR) Alus in 3′ UTRs, AU-rich elements, and RNA-binding proteins. SGs and processing bodies (P-bodies) transiently interact through a docking mechanism to allow the exchange of RNA species. However, the types of RNA species exchanged, and the mechanisms and outcomes of exchange are still unknown. Specialized RNA-binding proteins, including adenosine deaminase acting on RNA (ADAR1-p150), with an affinity toward inverted repeat Alus, and Tudor staphylococcal nuclease (Tudor-SN) are specifically recruited to SGs under OS along with an RNA transport protein, Staufen1 (STAU1), but their precise biochemical roles in SGs and SG/P-body docking are uncertain. Here, we critically review relevant literature and propose a hypothetical mechanism for the processing and decay of oxidized-RNA in SGs/P-bodies, as well as the role of ADAR1-p150, Tudor-SN, and STAU1.

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The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽

10.3390/antiox10040552 ◽

2021 ◽

Vol 10 (4) ◽

pp. 552

Author(s):

Jasmine Harley ◽

Benjamin E. Clarke ◽

Rickie Patani

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Mitochondrial Dysfunction ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Therapeutic Strategies ◽

Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

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DT-03-02: Viewing neurodegeneration beyond the tangle: The role of RNA binding proteins in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.08.014 ◽

2013 ◽

Vol 9 ◽

pp. P847-P847

Author(s):

Benjamin Wolozin ◽

Tara Vanderweyde ◽

Liqun Liu-Yesucevitz ◽

Alpaslan Dedeoglu ◽

Leonard Petrucelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins

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RNA Is a Double-Edged Sword in ALS Pathogenesis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.708181 ◽

2021 ◽

Vol 15 ◽

Author(s):

Benjamin L. Zaepfel ◽

Jeffrey D. Rothstein

Keyword(s):

Motor Neurons ◽

Cortical Neurons ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Small Subset ◽

Toxic Rna ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

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The Expanding Role of RNA-Binding Proteins in Neurodegeneration

Insights into Human Neurodegeneration: Lessons Learnt from Drosophila ◽

10.1007/978-981-13-2218-1_13 ◽

2019 ◽

pp. 373-403

Author(s):

Bhawana Maurya ◽

Satya Surabhi ◽

Pranjali Pandey ◽

Ashim Mukherjee ◽

Mousumi Mutsuddi

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins

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Role of ELAV-like RNA-binding proteins HuD and HuR in the post-transcriptional regulation of acetylcholinesterase in neurons and skeletal muscle cells

Chemico-Biological Interactions ◽

10.1016/j.cbi.2005.10.004 ◽

2005 ◽

Vol 157-158 ◽

pp. 43-49 ◽

Cited By ~ 12

Author(s):

Julie Deschênes-Furry ◽

Lindsay M. Angus ◽

Guy Bélanger ◽

James Mwanjewe ◽

Bernard J. Jasmin

Keyword(s):

Skeletal Muscle ◽

Transcriptional Regulation ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Post Transcriptional Regulation

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Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains

Biological Chemistry ◽

10.1515/hsz-2013-0111 ◽

2013 ◽

Vol 394 (8) ◽

pp. 1077-1090 ◽

Cited By ~ 45

Author(s):

Kristin Wächter ◽

Marcel Köhn ◽

Nadine Stöhr ◽

Stefan Hüttelmaier

Keyword(s):

Subcellular Localization ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Nuclear Accumulation ◽

Structural Constraints ◽

Cellular Functions ◽

Dependent Protein ◽

Mrna Binding

Abstract The IGF2 mRNA-binding protein family (IGF2BPs) directs the cytoplasmic fate of various target mRNAs and controls essential cellular functions. The three IGF2BP paralogues expressed in mammals comprise two RNA-recognition motifs (RRM) as well as four KH domains. How these domains direct IGF2BP paralogue-dependent protein function remains largely elusive. In this study, we analyze the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides. These analyses reveal that all four KH domains of IGF2BP1 and IGF2BP2 are essentially involved in RNA-binding in vitro and the cellular association with RNA-binding proteins (RBPs). Moreover the KH domains prevent the nuclear accumulation of these two paralogues and facilitate their recruitment to stress granules. The role of KH domains appears less pronounced in IGF2BP3, because GxxG-GEEG conversion in all four KH domains only modestly affects RNA-binding, subcellular localization and RNA-dependent protein association of this paralogue. These findings indicate paralogue-dependent RNA-binding properties of IGF2BPs which likely direct distinct cellular functions. Our findings suggest that IGF2BPs contact target RNAs via all four KH domains. This implies significant structural constraints, which presumably allow the formation of exceedingly stable protein-RNA complexes.

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