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Pesquisa : D12.776.157.725.813.750.905 [Categoria DeCS]
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[PMID]:29362359
[Au] Autor:Naumann M; Pal A; Goswami A; Lojewski X; Japtok J; Vehlow A; Naujock M; Günther R; Jin M; Stanslowsky N; Reinhardt P; Sterneckert J; Frickenhaus M; Pan-Montojo F; Storkebaum E; Poser I; Freischmidt A; Weishaupt JH; Holzmann K; Troost D; Ludolph AC; Boeckers TM; Liebau S; Petri S; Cordes N; Hyman AA; Wegner F; Grill SW; Weis J; Storch A; Hermann A
[Ad] Endereço:Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
[Ti] Título:Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation.
[So] Source:Nat Commun;9(1):335, 2018 01 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/metabolismo
Dano ao DNA
Neurônios Motores/metabolismo
Mutação
Agregação Patológica de Proteínas/metabolismo
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/genética
Idoso
Idoso de 80 Anos ou mais
Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/patologia
Diferenciação Celular
Núcleo Celular/metabolismo
Citoplasma/metabolismo
Feminino
Expressão Gênica
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Masculino
Meia-Idade
Neurônios Motores/patologia
Sinais de Localização Nuclear/genética
Sinais de Localização Nuclear/metabolismo
Poli(ADP-Ribose) Polimerase-1/genética
Poli(ADP-Ribose) Polimerase-1/metabolismo
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/patologia
Proteína FUS de Ligação a RNA/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nuclear Localization Signals); 0 (RNA-Binding Protein FUS); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02299-1


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[PMID]:28453628
[Au] Autor:Svetoni F; De Paola E; La Rosa P; Mercatelli N; Caporossi D; Sette C; Paronetto MP
[Ad] Endereço:Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy.
[Ti] Título:Post-transcriptional regulation of FUS and EWS protein expression by miR-141 during neural differentiation.
[So] Source:Hum Mol Genet;26(14):2732-2746, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Brain development involves proliferation, migration and specification of neural progenitor cells, culminating in neuronal circuit formation. Mounting evidence indicates that improper regulation of RNA binding proteins (RBPs), including members of the FET (FUS, EWS, TAF15) family, results in defective cortical development and/or neurodegenerative disorders. However, in spite of their physiological relevance, the precise pattern of FET protein expression in developing neurons is largely unknown. Herein, we found that FUS, EWS and TAF15 expression is differentially regulated during brain development, both in time and in space. In particular, our study identifies a fine-tuned regulation of FUS and EWS during neuronal differentiation, whereas TAF15 appears to be more constitutively expressed. Mechanistically FUS and EWS protein expression is regulated at the post-transcriptional level during neuron differentiation and brain development. Moreover, we identified miR-141 as a key regulator of these FET proteins that modulate their expression levels in differentiating neuronal cells. Thus, our studies uncover a novel link between post-transcriptional regulation of FET proteins expression and neurogenesis.
[Mh] Termos MeSH primário: MicroRNAs/metabolismo
Neurônios/fisiologia
Processamento Pós-Transcricional do RNA
Proteína EWS de Ligação a RNA/biossíntese
Proteína FUS de Ligação a RNA/biossíntese
[Mh] Termos MeSH secundário: Animais
Encéfalo/citologia
Encéfalo/embriologia
Encéfalo/metabolismo
Diferenciação Celular/fisiologia
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
MicroRNAs/genética
Neurogênese/fisiologia
Neurônios/citologia
Neurônios/metabolismo
Processamento de Proteína Pós-Traducional
Proteína EWS de Ligação a RNA/genética
Proteína EWS de Ligação a RNA/metabolismo
Proteína FUS de Ligação a RNA/genética
Proteína FUS de Ligação a RNA/metabolismo
Proteínas de Ligação a RNA/metabolismo
Fatores Associados à Proteína de Ligação a TATA/biossíntese
Fatores Associados à Proteína de Ligação a TATA/genética
Fatores Associados à Proteína de Ligação a TATA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (EWSR1 protein, human); 0 (FUS protein, human); 0 (FUS protein, mouse); 0 (MIRN141 microRNA, human); 0 (MicroRNAs); 0 (Mirn141 microRNA, mouse); 0 (RNA-Binding Protein EWS); 0 (RNA-Binding Protein FUS); 0 (RNA-Binding Proteins); 0 (TAF15 protein, human); 0 (TAF15 protein, mouse); 0 (TATA-Binding Protein Associated Factors)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx160


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[PMID]:29053787
[Au] Autor:Devoy A; Kalmar B; Stewart M; Park H; Burke B; Noy SJ; Redhead Y; Humphrey J; Lo K; Jaeger J; Mejia Maza A; Sivakumar P; Bertolin C; Soraru G; Plagnol V; Greensmith L; Acevedo Arozena A; Isaacs AM; Davies B; Fratta P; Fisher EMC
[Ad] Endereço:Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
[Ti] Título:Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.
[So] Source:Brain;140(11):2797-2805, 2017 Nov 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Modelos Animais de Doenças
Mutação da Fase de Leitura
Camundongos
Agregação Patológica de Proteínas/genética
Proteína FUS de Ligação a RNA/genética
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/metabolismo
Animais
Retículo Endoplasmático Rugoso/metabolismo
Dosagem de Genes
Perfilação da Expressão Gênica
Técnicas de Introdução de Genes
Heterozigoto
Seres Humanos
Mitocôndrias/metabolismo
Neurônios Motores/metabolismo
Junção Neuromuscular/metabolismo
Agregação Patológica de Proteínas/metabolismo
Proteína FUS de Ligação a RNA/metabolismo
Proteínas Ribossômicas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA-Binding Protein FUS); 0 (Ribosomal Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx248


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[PMID]:28977508
[Au] Autor:Bailey JK; Shen W; Liang XH; Crooke ST
[Ad] Endereço:Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA 92010, USA.
[Ti] Título:Nucleic acid binding proteins affect the subcellular distribution of phosphorothioate antisense oligonucleotides.
[So] Source:Nucleic Acids Res;45(18):10649-10671, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Antisense oligonucleotides (ASOs) are versatile tools that can regulate multiple steps of RNA biogenesis in cells and living organisms. Significant improvements in delivery, potency, and stability have been achieved through modifications within the oligonucleotide backbone, sugar and heterocycles. However, these modifications can profoundly affect interactions between ASOs and intracellular proteins in ways that are only beginning to be understood. Here, we report that ASOs with specific backbone and sugar modifications can become localized to cytoplasmic ribonucleoprotein granules such as stress granules and those seeded by the aggregation of specific ASO-binding proteins such as FUS/TLS (FUS) and PSF/SFPQ (PSF). Further investigation into the basis for ASO-FUS binding illustrated the importance of ASO backbone and hydrophobic 2' sugar modifications and revealed that the C-terminal region of FUS is sufficient to retain ASOs in cellular foci. Taken together, the results of this study demonstrate that affinities of various nucleic acid binding domains for ASO depend on chemical modifications and further demonstrate how ASO-protein interactions influence the localization of ASOs.
[Mh] Termos MeSH primário: Oligonucleotídeos Antissenso/análise
Fator de Processamento Associado a PTB/metabolismo
Oligonucleotídeos Fosforotioatos/análise
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Núcleo Celular/química
Grânulos Citoplasmáticos/química
Seres Humanos
Mutação
Oligonucleotídeos Antissenso/química
Oligonucleotídeos Antissenso/metabolismo
Fator de Processamento Associado a PTB/genética
Oligonucleotídeos Fosforotioatos/química
Oligonucleotídeos Fosforotioatos/metabolismo
Agregados Proteicos
Ligação Proteica
Proteína-Arginina N-Metiltransferases/metabolismo
Proteína FUS de Ligação a RNA/análise
Proteína FUS de Ligação a RNA/química
Proteína FUS de Ligação a RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligonucleotides, Antisense); 0 (PTB-Associated Splicing Factor); 0 (Phosphorothioate Oligonucleotides); 0 (Protein Aggregates); 0 (RNA-Binding Protein FUS); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx709


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[PMID]:28942918
[Au] Autor:Murray DT; Kato M; Lin Y; Thurber KR; Hung I; McKnight SL; Tycko R
[Ad] Endereço:Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA; Postdoctoral Research Associate Program, National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD 20892-62
[Ti] Título:Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains.
[So] Source:Cell;171(3):615-627.e16, 2017 Oct 19.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Polymerization and phase separation of proteins containing low-complexity (LC) domains are important factors in gene expression, mRNA processing and trafficking, and localization of translation. We have used solid-state nuclear magnetic resonance methods to characterize the molecular structure of self-assembling fibrils formed by the LC domain of the fused in sarcoma (FUS) RNA-binding protein. From the 214-residue LC domain of FUS (FUS-LC), a segment of only 57 residues forms the fibril core, while other segments remain dynamically disordered. Unlike pathogenic amyloid fibrils, FUS-LC fibrils lack hydrophobic interactions within the core and are not polymorphic at the molecular structural level. Phosphorylation of core-forming residues by DNA-dependent protein kinase blocks binding of soluble FUS-LC to FUS-LC hydrogels and dissolves phase-separated, liquid-like FUS-LC droplets. These studies offer a structural basis for understanding LC domain self-assembly, phase separation, and regulation by post-translational modification.
[Mh] Termos MeSH primário: Proteína FUS de Ligação a RNA/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Seres Humanos
Microscopia de Força Atômica
Microscopia Eletrônica de Transmissão
Modelos Moleculares
Ressonância Magnética Nuclear Biomolecular
Fosforilação
Domínios Proteicos
Proteína FUS de Ligação a RNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FUS protein, human); 0 (RNA-Binding Protein FUS)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


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[PMID]:28912172
[Au] Autor:Conlon EG; Manley JL
[Ad] Endereço:Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
[Ti] Título:RNA-binding proteins in neurodegeneration: mechanisms in aggregate.
[So] Source:Genes Dev;31(15):1509-1528, 2017 08 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.
[Mh] Termos MeSH primário: Doenças Neurodegenerativas/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Envelhecimento
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Seres Humanos
Repetições de Microssatélites/genética
Doenças Neurodegenerativas/genética
Neurônios/metabolismo
Organelas/metabolismo
RNA/metabolismo
Processamento Pós-Transcricional do RNA
Proteína FUS de Ligação a RNA/genética
Proteína FUS de Ligação a RNA/metabolismo
Proteínas de Ligação a RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (RNA-Binding Protein FUS); 0 (RNA-Binding Proteins); 0 (TDP-43 protein, human); 63231-63-0 (RNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1101/gad.304055.117


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[PMID]:28817800
[Au] Autor:Mackenzie IR; Nicholson AM; Sarkar M; Messing J; Purice MD; Pottier C; Annu K; Baker M; Perkerson RB; Kurti A; Matchett BJ; Mittag T; Temirov J; Hsiung GR; Krieger C; Murray ME; Kato M; Fryer JD; Petrucelli L; Zinman L; Weintraub S; Mesulam M; Keith J; Zivkovic SA; Hirsch-Reinshagen V; Roos RP; Züchner S; Graff-Radford NR; Petersen RC; Caselli RJ; Wszolek ZK; Finger E; Lippa C; Lacomis D; Stewart H; Dickson DW; Kim HJ; Rogaeva E; Bigio E; Boylan KB; Taylor JP; Rademakers R
[Ad] Endereço:Department of Pathology and Laboratory Medicine, Vancouver Coastal Health and the University of British Colombia, Vancouver, BC V6T 2B5, Canada.
[Ti] Título:TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.
[So] Source:Neuron;95(4):808-816.e9, 2017 Aug 16.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10 ). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/patologia
Demência Frontotemporal/genética
Demência Frontotemporal/patologia
Mutação/genética
Proteínas de Ligação a Poli(A)/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Proteínas de Ligação a DNA/metabolismo
Saúde da Família
Feminino
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HeLa
Ribonucleoproteína Nuclear Heterogênea A1
Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo
Seres Humanos
Masculino
Microscopia Confocal
Meia-Idade
Proteína FUS de Ligação a RNA/metabolismo
Estresse Fisiológico/fisiologia
Antígeno-1 Intracelular de Células T
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (FUS protein, human); 0 (Heterogeneous Nuclear Ribonucleoprotein A1); 0 (Heterogeneous-Nuclear Ribonucleoprotein Group A-B); 0 (Poly(A)-Binding Proteins); 0 (RNA-Binding Protein FUS); 0 (T-Cell Intracellular Antigen-1); 0 (TDP-43 protein, human); 0 (TIA1 protein, human); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE


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[PMID]:28790177
[Au] Autor:Monahan Z; Ryan VH; Janke AM; Burke KA; Rhoads SN; Zerze GH; O'Meally R; Dignon GL; Conicella AE; Zheng W; Best RB; Cole RN; Mittal J; Shewmaker F; Fawzi NL
[Ad] Endereço:Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, Bethesda, MD, USA.
[Ti] Título:Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity.
[So] Source:EMBO J;36(20):2951-2967, 2017 Oct 16.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neuronal inclusions of aggregated RNA-binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation-prone, yeast prion-like, low sequence-complexity domain (LC) is known to be targeted for phosphorylation. Here we map and in-cell phosphorylation sites across FUS LC We show that both phosphorylation and phosphomimetic variants reduce its aggregation-prone/prion-like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self-interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS-associated cytotoxicity. Hence, post-translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.
[Mh] Termos MeSH primário: Processamento de Proteína Pós-Traducional
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/patologia
Linhagem Celular
Demência Frontotemporal/patologia
Seres Humanos
Espectroscopia de Ressonância Magnética
Fosforilação
Agregação Patológica de Proteínas
Conformação Proteica
Proteína FUS de Ligação a RNA/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FUS protein, human); 0 (RNA-Binding Protein FUS)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201696394


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[PMID]:28707655
[Au] Autor:Efimova AD; Ovchinnikov RK; Roman AY; Maltsev AV; Grigoriev VV; Kovrazhkina EA; Skvortsova VI
[Ad] Endereço:Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia.
[Ti] Título:[The FUS protein: Physiological functions and a role in amyotrophic lateral sclerosis].
[So] Source:Mol Biol (Mosk);51(3):387-399, 2017 May-Jun.
[Is] ISSN:0026-8984
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Certain forms of amyotrophic lateral sclerosis (ALS) are associated with an altered compartmentalization of FUS and its aggregation in the cytoplasm of motoneurons. FUS is a DNA/RNA-binding protein that is involved in DNA repair and the regulation of transcription, splicing, RNA transport, and local translation. Two theories have been proposed to explain the mechanism of the pathophysiological process in ALS. The theories attribute degeneration of motor neurons to either loss or gain of FUS function. The review describes the main physiological functions of FUS and considers evidence for each of the theories of ALS pathogenesis.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Neurônios Motores/metabolismo
Agregação Patológica de Proteínas/genética
Proteína FUS de Ligação a RNA/genética
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/patologia
Reparo do DNA/genética
Seres Humanos
Neurônios Motores/patologia
Processamento de RNA/genética
Proteína FUS de Ligação a RNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (RNA-Binding Protein FUS)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.7868/S0026898417020094


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[PMID]:28575444
[Au] Autor:Ozdilek BA; Thompson VF; Ahmed NS; White CI; Batey RT; Schwartz JC
[Ad] Endereço:Department of Molecular, Cellular and Developmental Biology, University of Colorado, Campus Box 347, Boulder, CO 80309, USA.
[Ti] Título:Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding.
[So] Source:Nucleic Acids Res;45(13):7984-7996, 2017 Jul 27.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:RGG/RG domains are the second most common RNA binding domain in the human genome, yet their RNA-binding properties remain poorly understood. Here, we report a detailed analysis of the RNA binding characteristics of intrinsically disordered RGG/RG domains from Fused in Sarcoma (FUS), FMRP and hnRNPU. For FUS, previous studies defined RNA binding as mediated by its well-folded domains; however, we show that RGG/RG domains are the primary mediators of binding. RGG/RG domains coupled to adjacent folded domains can achieve affinities approaching that of full-length FUS. Analysis of RGG/RG domains from FUS, FMRP and hnRNPU against a spectrum of contrasting RNAs reveals that each display degenerate binding specificity, while still displaying different degrees of preference for RNA.
[Mh] Termos MeSH primário: Proteínas Intrinsicamente Desordenadas/metabolismo
RNA/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína do X Frágil de Retardo Mental/química
Proteína do X Frágil de Retardo Mental/metabolismo
Quadruplex G
Células HEK293
Ribonucleoproteínas Nucleares Heterogêneas Grupo U/química
Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo
Seres Humanos
Proteínas Intrinsicamente Desordenadas/química
Camundongos
Modelos Biológicos
Ligação Proteica
Domínios Proteicos
RNA/química
Proteína FUS de Ligação a RNA/química
Proteína FUS de Ligação a RNA/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein U); 0 (Intrinsically Disordered Proteins); 0 (RNA-Binding Protein FUS); 0 (Recombinant Proteins); 0 (SAF-A protein, human); 139135-51-6 (Fragile X Mental Retardation Protein); 63231-63-0 (RNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx460



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