Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons

Liu, Elaine Y.; Russ, Jenny; Cali, Christopher P.; Phan, Jessica M.; Amlie‐Wolf, Alexandre; Lee, Edward B.

doi:10.1016/j.celrep.2019.04.003

Cited by 157 publications

(253 citation statements)

References 84 publications

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“…Moreover, the connection between TDP-43 and transposable elements has only recently been explored. While previous studies have linked TDP-43 to transposon binding in human cells and to transposon regulation in animal models (Chang and Dubnau, 2019;Krug et al, 2017;Li et al, 2015;Liu et al, 2019), we show that TDP-4-bound transposon transcripts are de-silenced in human cells and demonstrate that these same targets are de-silenced in a subset of human ALS patients. Additional mechanisms for transposon de-silencing in ALS patients with C9orf72 repeat expansions have been suggested (Pereira et al, 2018;Prudencio et al, 2017;Zhang et al, 2019), although we note that C9orf72 status was not strongly associated with the ALS-TE group in this study.…”

Section: Discussioncontrasting

confidence: 62%

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

et al. 2019

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AUTHOR CONTRIBUTIONS O.H.T., M.G.H., and J.D. designed the study. N.V.R. designed and performed the experiments identifying TDP-43 targets in SH-SY5Y cells. R.S. designed and performed the experiments on the UCSD ALS patient samples. J.R. provided the UCSD ALS patient samples and associated clinical and diagnostic data. In the NYGC ALS Consortium, members contributed ALS patient samples and clinical information. D.K. curated de-identified clinical data and C9orf72 genotype information. I.H. and N.P. coordinated study materials and processed samples for sequencing. S.F. oversees Consortium resources and data distribution. D.F. and H.P. designed the methodology, reviewed sample preparation and data quality, and coordinated the research activity of NYGC ALS Consortium postmortem core RNA-seq experiments. B.T.H. supervised the neuropathological analysis of the immunohistochemical staining results. L.W.O. coordinated the post-mortem tissue, slide, and data collection through the Target ALS Multicenter Post-Mortem Tissue Core and assisted in analysis of the immunohistochemical staining results. O.H.T. and M.G.H. analyzed the data. All authors contributed to the interpretation, writing, and editing of the manuscript.

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Section: Discussioncontrasting

confidence: 62%

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

et al. 2019

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“…Among the RBPs screened in this study, only Staufen was identified as a dsRBP. This is a significant point, because what most distinguishes Staufen from other RBPs screened is its ability to bind to dsRNA [34], a toxic byproduct of disrupted heterochromatin caused by PR toxicity [14] and nuclear loss of TDP-43 [13, 23, 24]. In this study, we showed that V5-PR36 expression led to increased co-localization of Staufen with heterochromatin and that degrading RNAs via RNase led to decreased nuclear accumulation of Staufen.…”

Section: Discussionmentioning

confidence: 73%

“…Next, we asked how PR toxicity might induce nuclear accumulation of dsRNA in C4 da neurons. Recent studies showed that loss of nuclear TDP-43, a prominent pathological feature of C9-ALS/FTD [22], can derepress RE transcription from heterochromatin [13, 23, 24], leading to accumulation of dsRNA in the nucleus. Thus we tested whether decreasing the amount of nuclear TBPH, a Drosophila ortholog of TDP-43, is sufficient to increase accumulation of Staufen in the nucleus.…”

Section: Resultsmentioning

confidence: 99%

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Kim

Chung

Kim

et al. 2019

Preprint

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25Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated 26 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential 27 42 Staufen, may also be an important pathological feature of C9-ALS/FTD. 43 44 45 46 47 3 48 Author summary 49 Cytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common 50 pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia 51 (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded 52 (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-53 dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that 54 Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression 55 of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity 56 and further augmented by reduction in stau dosage, the gene encoding Staufen. When we 57 knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was 58 exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is 59 protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their 60 retinal degeneration and viability were largely rescued. Based on these data, we suggest that 61 nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that 62 reducing stau dosage is a promising therapeutic target.

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“…Es por ello que su empleo en patologías complejas resulta de gran utilizad, como en el caso de la ELA, una enfermedad neurodegenerativa que se caracteriza por la progresiva disminución y atrofia de masa neuromuscular debido a la pérdida de motoneuronas (MN) [2], del tronco espinal y del cortex motor [3]. Como ocurre en este tipo de enfermedades, los mecanismos moleculares que dan lugar a esta neurodegeneración no están claramente definidos en la actualidad.…”

Section: Introductionunclassified

“…En condiciones fisiológicas, TDP-43 presenta una localización nuclear y se encuentra regulando muchas y diversas funciones implicadas en el procesamiento del ARN. En esta enfermedad disminuye su localización nuclear y se acumula en el citoplasma en forma de agregados [2]. En concreto aparece ubiquitinada e hiperfosforilada formando cuerpos de inclusión en el citoplasma de neuronas de la médula espinal de pacientes con ELA, pero también se ha detectado en pacientes con otras enfermedades neurodegenerativas como son la demencia frontotemporal y la enfemedad de Alzheimer.…”

Section: Introductionunclassified

Estudio del potencial de bioconjugados Quantum Dots para el marcaje específico de dianas involucradas en Esclerosis Lateral Amiotrófica

Sánchez¹,

Bitrián²,

Palomo³

2019

DIANAS

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Palabras clave: Multicolor Multicycle Molecular profiling (M3P); esclerosis lateral amiotrófica (ELA); Quantum Dots (QDs); inmunoensayo ResumenLa investigación biomédica se encuentra en continuo avance y requiere la implantación de técnicas novedosas y prometedoras que permitan esclarecer mecanismos de enfermedades y seleccionar medicamentos eficaces para las mismas. El fin de estas técnicas es poder aplicar un tratamiento individualizado a cada paciente, es decir, implantar la medicina personalizada y para ello son necesarios biomarcadores y sensores efectivos. La técnica Multicolor Multicycle Molecular profiling (M3P), la cual se quiere aplicar en patologías de gran complejidad molecular como la esclerosis lateral amiotrofia (ELA), entre otras, utiliza Quantum Dots (QDs), nanopartículas con características fotoluminiscentes únicas y ventajosas sobre los fluoróforos tradicionales y con gran potencial como herramienta puntera en el campo de la biomedicina. En este trabajo se muestran los resultados obtenidos tras la realización de distintos inmunoensayos de QDs para estudiar su efectividad de marcaje de proteínas, la penetrabilidad en el núcleo y en consecuencia su potencial para seleccionar fármacos eficaces para patologías complejas como la ELA. Cita: Baños Sánchez, Nerea; Tosat-Bitrián, Carlota; Palomo, Valle (2019) Estudio del potencial de bioconjugados Quantum Dots para el marcaje específico de dianas involucradas en Esclerosis Lateral Amiotrófica. dianas 8 (2): e201909fa08. ISSN 1886-8746 (electronic) journal.dianas.e201909fa08 Copyright: © Baños-Sánchez N, Tosat--Bitrián C, Palomo V. Algunos derechos reservados. Este es un artículo open-access distribuido bajo los términos de una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional. http://creativecommons.org/licenses/by-nc-nd/4.0/

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Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons

Cited by 157 publications

References 84 publications

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Estudio del potencial de bioconjugados Quantum Dots para el marcaje específico de dianas involucradas en Esclerosis Lateral Amiotrófica

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