Publications by authors named "Coralie Viollet"

11 Publications

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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Authors:
Ruth Chia Marya S Sabir Sara Bandres-Ciga Sara Saez-Atienzar Regina H Reynolds Emil Gustavsson Ronald L Walton Sarah Ahmed Coralie Viollet Jinhui Ding Mary B Makarious Monica Diez-Fairen Makayla K Portley Zalak Shah Yevgeniya Abramzon Dena G Hernandez Cornelis Blauwendraat David J Stone John Eicher Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S Honig Karen Marder Afina Lemstra Peter St George-Hyslop Elisabet Londos Kevin Morgan Tammaryn Lashley Thomas T Warner Zane Jaunmuktane Douglas Galasko Isabel Santana Pentti J Tienari Liisa Myllykangas Minna Oinas Nigel J Cairns John C Morris Glenda M Halliday Vivianna M Van Deerlin John Q Trojanowski Maurizio Grassano Andrea Calvo Gabriele Mora Antonio Canosa Gianluca Floris Ryan C Bohannan Francesca Brett Ziv Gan-Or Joshua T Geiger Anni Moore Patrick May Rejko Krüger David S Goldstein Grisel Lopez Nahid Tayebi Ellen Sidransky Lucy Norcliffe-Kaufmann Jose-Alberto Palma Horacio Kaufmann Vikram G Shakkottai Matthew Perkins Kathy L Newell Thomas Gasser Claudia Schulte Francesco Landi Erika Salvi Daniele Cusi Eliezer Masliah Ronald C Kim Chad A Caraway Edwin S Monuki Maura Brunetti Ted M Dawson Liana S Rosenthal Marilyn S Albert Olga Pletnikova Juan C Troncoso Margaret E Flanagan Qinwen Mao Eileen H Bigio Eloy Rodríguez-Rodríguez Jon Infante Carmen Lage Isabel González-Aramburu Pascual Sanchez-Juan Bernardino Ghetti Julia Keith Sandra E Black Mario Masellis Ekaterina Rogaeva Charles Duyckaerts Alexis Brice Suzanne Lesage Georgia Xiromerisiou Matthew J Barrett Bension S Tilley Steve Gentleman Giancarlo Logroscino Geidy E Serrano Thomas G Beach Ian G McKeith Alan J Thomas Johannes Attems Christopher M Morris Laura Palmer Seth Love Claire Troakes Safa Al-Sarraj Angela K Hodges Dag Aarsland Gregory Klein Scott M Kaiser Randy Woltjer Pau Pastor Lynn M Bekris James B Leverenz Lilah M Besser Amanda Kuzma Alan E Renton Alison Goate David A Bennett Clemens R Scherzer Huw R Morris Raffaele Ferrari Diego Albani Stuart Pickering-Brown Kelley Faber Walter A Kukull Estrella Morenas-Rodriguez Alberto Lleó Juan Fortea Daniel Alcolea Jordi Clarimon Mike A Nalls Luigi Ferrucci Susan M Resnick Toshiko Tanaka Tatiana M Foroud Neill R Graff-Radford Zbigniew K Wszolek Tanis Ferman Bradley F Boeve John A Hardy Eric J Topol Ali Torkamani Andrew B Singleton Mina Ryten Dennis W Dickson Adriano Chiò Owen A Ross J Raphael Gibbs Clifton L Dalgard Bryan J Traynor Sonja W Scholz

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Neuron 2021 02 26;109(3):448-460.e4. Epub 2020 Nov 26.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA. Electronic address:

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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http://dx.doi.org/10.1016/j.neuron.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864894PMC
February 2021

SMN-deficiency disrupts SERCA2 expression and intracellular Ca signaling in cardiomyocytes from SMA mice and patient-derived iPSCs.

Skelet Muscle 2020 05 8;10(1):16. Epub 2020 May 8.

Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Bethesda, MD, USA.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed, and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T for Ca sequestration increased to 146 ± 4 ms in SMN-deficient cardiomyocytes from 126 ± 4 ms in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent-derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca cycling dysregulation.
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http://dx.doi.org/10.1186/s13395-020-00232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206821PMC
May 2020

Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer.

Cell Rep 2020 04;31(2):107502

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC), which is the most lethal gynecologic malignancy, is not well understood. Here, we perform comprehensive multi-platform omics analyses, including integrated analysis, and immune monitoring on primary and metastatic sites from highly clinically annotated HGSC samples based on a laparoscopic triage algorithm from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT) with excellent or poor response. We identify significant distinct molecular abnormalities and cellular changes and immune cell repertoire alterations between the groups, including a higher rate of NF1 copy number loss, and reduced chromothripsis-like patterns, higher levels of strong-binding neoantigens, and a higher number of infiltrated T cells in the R0 versus the NACT groups.
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http://dx.doi.org/10.1016/j.celrep.2020.03.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234854PMC
April 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Neuroinflammatory astrocytes generated from cord blood-derived human induced pluripotent stem cells.

J Neuroinflammation 2019 Aug 9;16(1):164. Epub 2019 Aug 9.

Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.

Background: Astrocytes respond to central nervous system (CNS) injury and disease by transforming to a reactive astrogliosis cell state that can contribute to either CNS dysfunction or repair. Neuroinflammation is a powerful driver of a harmful A1 astrogliosis phenotype associated with in vitro neurotoxicity and histopathology in human neurodegenerative diseases. Here we report a protocol for the rapid development of a human cell culture model of neuroinflammatory astrogliosis using induced pluripotent stem cells (iPSCs).

Methods: Using RNA sequencing and in vitro cell assays, we measured transcriptional and cellular effects of chronic exposure of human iPSC-derived astrocytes to the cytokines TNFα (tumor necrosis factor alpha) or IL-1β (interleukin-1 beta).

Results: We show TNFα and IL-1β induce pro-inflammatory gene signatures but by widely different magnitudes. TNFα treatment results in 606 differential expressed genes, the suppression of glutamate-uptake, and increased phagocytic activity in astrocyte cultures. In contrast, IL-1β effects are attenuated to 33 differential expressed genes and no significant effects on glutamate-uptake or increased phagocytic activity.

Conclusion: Our approach demonstrates a rapid tool for modeling neuroinflammatory human astrocytic responses in nervous system trauma and disease. In particular, we reveal a model for robust TNFα-induced human astrogliosis suitable for the study of neurotoxic A1 astrocytes.
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http://dx.doi.org/10.1186/s12974-019-1553-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688278PMC
August 2019

DMSO cryopreservation is the method of choice to preserve cells for droplet-based single-cell RNA sequencing.

Sci Rep 2019 07 23;9(1):10699. Epub 2019 Jul 23.

Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach, Germany.

Combining single-cell RNA sequencing (scRNA-seq) with upstream cell preservation procedures such as cryopreservation or methanol fixation has recently become more common. By separating cell handling and preparation, from downstream library generation, scRNA-seq workflows are more flexible and manageable. However, the inherent transcriptomic changes associated with cell preservation and how they may bias further downstream analysis remain unknown. Here, we present a side-by-side droplet-based scRNA-seq analysis, comparing the gold standard - fresh cells - to three different cell preservation workflows: dimethyl sulfoxide based cryopreservation, methanol fixation and CellCover reagent. Cryopreservation proved to be the most robust protocol, maximizing both cell integrity and low background ambient RNA. Importantly, gene expression profiles from fresh cells correlated most with those of cryopreserved cells. Such similarities were consistently observed across the tested cell lines (R ≥ 0.97), monocyte-derived macrophages (R = 0.97) and immune cells (R = 0.99). In contrast, both methanol fixation and CellCover preservation showed an increased ambient RNA background and an overall lower gene expression correlation to fresh cells. Thus, our results demonstrate the superiority of cryopreservation over other cell preservation methods. We expect our comparative study to provide single-cell omics researchers invaluable support when integrating cell preservation into their scRNA-seq studies.
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http://dx.doi.org/10.1038/s41598-019-46932-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650608PMC
July 2019

Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma.

PLoS Pathog 2017 Sep 18;13(9):e1006628. Epub 2017 Sep 18.

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1α, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1α activity, and several KSHV genes are in turn activated by HIF-1α. In this study, we investigated the effects of knocking down HIF-1α in PELs. We observed that HIF-1α knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1α is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1α suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1α knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1α plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1α suppression achieved by either HIF-1α knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1α. These results offer further evidence that HIF-1α plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1α can be a potential therapeutic strategy in this disease.
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http://dx.doi.org/10.1371/journal.ppat.1006628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619862PMC
September 2017

The role of the immunoproteasome in interferon-γ-mediated microglial activation.

Sci Rep 2017 08 24;7(1):9365. Epub 2017 Aug 24.

Neuroscience Program, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD, USA.

Microglia regulate the brain microenvironment by sensing damage and neutralizing potentially harmful insults. Disruption of central nervous system (CNS) homeostasis results in transition of microglia to a reactive state characterized by morphological changes and production of cytokines to prevent further damage to CNS tissue. Immunoproteasome levels are elevated in activated microglia in models of stroke, infection and traumatic brain injury, though the exact role of the immunoproteasome in neuropathology remains poorly defined. Using gene expression analysis and native gel electrophoresis we characterize the expression and assembly of the immunoproteasome in microglia following interferon-gamma exposure. Transcriptome analysis suggests that the immunoproteasome regulates multiple features of microglial activation including nitric oxide production and phagocytosis. We show that inhibiting the immunoproteasome attenuates expression of pro-inflammatory cytokines and suppresses interferon-gamma-dependent priming of microglia. These results imply that targeting immunoproteasome function following CNS injury may attenuate select microglial activity to improve the pathophysiology of neurodegenerative conditions or the progress of inflammation-mediated secondary injury following neurotrauma.
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http://dx.doi.org/10.1038/s41598-017-09715-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571106PMC
August 2017

RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature.

PLoS Pathog 2017 01 3;13(1):e1006143. Epub 2017 Jan 3.

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.
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http://dx.doi.org/10.1371/journal.ppat.1006143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234848PMC
January 2017

Next-Generation Sequencing Analysis Reveals Differential Expression Profiles of MiRNA-mRNA Target Pairs in KSHV-Infected Cells.

PLoS One 2015 5;10(5):e0126439. Epub 2015 May 5.

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Kaposi's sarcoma associated herpesvirus (KSHV) causes several tumors, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). Cellular and viral microRNAs (miRNAs) have been shown to play important roles in regulating gene expression. A better knowledge of the miRNA-mediated pathways affected by KSHV infection is therefore important for understanding viral infection and tumor pathogenesis. In this study, we used deep sequencing to analyze miRNA and cellular mRNA expression in a cell line with latent KSHV infection (SLKK) as compared to the uninfected SLK line. This approach revealed 153 differentially expressed human miRNAs, eight of which were independently confirmed by qRT-PCR. KSHV infection led to the dysregulation of ~15% of the human miRNA pool and most of these cellular miRNAs were down-regulated, including nearly all members of the 14q32 miRNA cluster, a genomic locus linked to cancer and that is deleted in a number of PEL cell lines. Furthermore, we identified 48 miRNAs that were associated with a total of 1,117 predicted or experimentally validated target mRNAs; of these mRNAs, a majority (73%) were inversely correlated to expression changes of their respective miRNAs, suggesting miRNA-mediated silencing mechanisms were involved in a number of these alterations. Several dysregulated miRNA-mRNA pairs may facilitate KSHV infection or tumor formation, such as up-regulated miR-708-5p, associated with a decrease in pro-apoptotic caspase-2 and leukemia inhibitory factor LIF, or down-regulated miR-409-5p, associated with an increase in the p53-inhibitor MDM2. Transfection of miRNA mimics provided further evidence that changes in miRNAs are driving some observed mRNA changes. Using filtered datasets, we also identified several canonical pathways that were significantly enriched in differentially expressed miRNA-mRNA pairs, such as the epithelial-to-mesenchymal transition and the interleukin-8 signaling pathways. Overall, our data provide a more detailed understanding of KSHV latency and guide further studies of the biological significance of these changes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420468PMC
April 2016