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Journal Articles Nature Medicine Year : 2018

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Vivek Swarup (1) , Flora Hinz (1) , Jessica Rexach (1) , Ken-Ichi Noguchi , Hiroyoshi Toyoshiba , Akira Oda , Keisuke Hirai , Arjun Sarkar (1) , Nicholas Seyfried (2) , Chialin Cheng (3) , Stephen Haggarty (3) , Murray Grossman (4) , Vivianna van Deerlin (4) , John Trojanowski (4) , James Lah (2) , Allan Levey (2) , Shinichi Kondou , Daniel Geschwind (1, 5) , Raffaele Ferrari , Jonathan Rohrer , Adaikalavan Ramasamy , John Hardy , Dena Hernandez , Michael Nalls , Andrew Singleton , John Kwok , Carol Dobson-Stone , William Brooks , Peter Schofield , Glenda Halliday , John Hodges , Olivier Piguet , Lauren Bartley , Elizabeth Thompson , Eric Haan , Isabel Hernández , Agustín Ruiz , Mercè Boada , Barbara Borroni , Alessandro Padovani , Nigel Cairns , Carlos Cruchaga , Giuliano Binetti , Roberta Ghidoni , Luisa Benussi , Gianluigi Forloni , Diego Albani , Daniela Galimberti , Chiara Fenoglio , Maria Serpente , Elio Scarpini , Jordi Clarimón , Alberto Lleó , Rafael Blesa , Maria Landqvist Waldö , Karin Nilsson , Christer Nilsson , Ian Mackenzie , Ging-Yuek Hsiung , David Mann , Jordan Grafman , Christopher Morris , Johannes Attems , Timothy Griffiths , Ian Mckeith , Alan Thomas , Evelyn Jaros , Pietro Pietrini , Edward Huey , Eric Wassermann , Michael Tierney , Atik Baborie , Pau Pastor , Sara Ortega-Cubero , Cristina Razquin , Elena Alonso , Robert Perneczky , Janine Diehl-Schmid , Panagiotis Alexopoulos , Alexander Kurz , Innocenzo Rainero , Elisa Rubino , Lorenzo Pinessi , Ekaterina Rogaeva , Peter St. George-Hyslop , Giacomina Rossi , Fabrizio Tagliavini , Giorgio Giaccone , James Rowe , Johannes Schlachetzki , James Uphill , John Collinge , Simon Mead , Adrian Danek , Stuart Pickering-Brown , Parastoo Momeni , Julie van der Zee , Marc Cruts , Christine van Broeckhoven , Stefano Cappa , Isabelle Leber (6) , Alexis Brice (6) , Didier Hannequin , Véronique Golfier , Martine Vercelletto , Benedetta Nacmias , Sandro Sorbi , Silvia Bagnoli , Irene Piaceri , Jørgen Nielsen , Lena Hjermind , Matthias Riemenschneider , Manuel Mayhaus , Gilles Gasparoni , Sabrina Pichler , Bernd Ibach , Martin Rossor , Nick Fox , Jason Warren , Maria Grazia Spillantini , Huw Morris , Patrizia Rizzu , Peter Heutink , Julie Snowden , Sara Rollinson , Alexander Gerhard , Anna Richardson , Amalia Bruni , Raffaele Maletta , Francesca Frangipane , Chiara Cupidi , Livia Bernardi , Maria Anfossi , Maura Gallo , Maria Elena Conidi , Nicoletta Smirne , Rosa Rademakers , Matt Baker , Dennis Dickson , Neill Graff-Radford , Ronald Petersen , David Knopman , Keith Josephs , Bradley Boeve , Joseph Parisi , Bruce Miller , Anna Karydas , Howard Rosen , William Seeley , John van Swieten , Elise Dopper , Harro Seelaar , Yolande Pijnenburg , Philip Scheltens , Giancarlo Logroscino , Rosa Capozzo , Valeria Novelli , Annibale Puca , Massimo Franceschi , Alfredo Postiglione , Graziella Milan , Paolo Sorrentino , Mark Kristiansen , Huei-Hsin Chiang , Caroline Graff , Florence Pasquier , Adeline Rollin , Vincent Deramecourt , Thibaud Lebouvier , Luigi Ferrucci , Dimitrios Kapogiannis
Ken-Ichi Noguchi
  • Function : Author
Hiroyoshi Toyoshiba
  • Function : Author
Akira Oda
  • Function : Author
Keisuke Hirai
  • Function : Author
Vivianna van Deerlin
Shinichi Kondou
  • Function : Author
Raffaele Ferrari
  • Function : Author
Jonathan Rohrer
  • Function : Author
Adaikalavan Ramasamy
  • Function : Author
John Hardy
  • Function : Author
Dena Hernandez
  • Function : Author
Michael Nalls
  • Function : Author
Andrew Singleton
  • Function : Author
John Kwok
  • Function : Author
Carol Dobson-Stone
  • Function : Author
William Brooks
  • Function : Author
Peter Schofield
  • Function : Author
Glenda Halliday
  • Function : Author
John Hodges
  • Function : Author
Olivier Piguet
  • Function : Author
Lauren Bartley
  • Function : Author
Elizabeth Thompson
  • Function : Author
Eric Haan
  • Function : Author
Isabel Hernández
  • Function : Author
Agustín Ruiz
  • Function : Author
Mercè Boada
  • Function : Author
Barbara Borroni
  • Function : Author
Alessandro Padovani
  • Function : Author
Nigel Cairns
  • Function : Author
Carlos Cruchaga
  • Function : Author
Giuliano Binetti
  • Function : Author
Roberta Ghidoni
  • Function : Author
Luisa Benussi
  • Function : Author
Gianluigi Forloni
  • Function : Author
Diego Albani
  • Function : Author
Daniela Galimberti
  • Function : Author
Chiara Fenoglio
  • Function : Author
Maria Serpente
  • Function : Author
Elio Scarpini
  • Function : Author
Jordi Clarimón
  • Function : Author
Alberto Lleó
  • Function : Author
Rafael Blesa
  • Function : Author
Maria Landqvist Waldö
  • Function : Author
Karin Nilsson
  • Function : Author
Christer Nilsson
  • Function : Author
Ian Mackenzie
  • Function : Author
Ging-Yuek Hsiung
  • Function : Author
David Mann
  • Function : Author
Jordan Grafman
  • Function : Author
Christopher Morris
  • Function : Author
Johannes Attems
  • Function : Author
Timothy Griffiths
  • Function : Author
Ian Mckeith
  • Function : Author
Alan Thomas
  • Function : Author
Evelyn Jaros
  • Function : Author
Pietro Pietrini
  • Function : Author
Edward Huey
  • Function : Author
Eric Wassermann
  • Function : Author
Michael Tierney
  • Function : Author
Atik Baborie
  • Function : Author
Pau Pastor
  • Function : Author
Sara Ortega-Cubero
  • Function : Author
Cristina Razquin
  • Function : Author
Elena Alonso
  • Function : Author
Robert Perneczky
  • Function : Author
Janine Diehl-Schmid
  • Function : Author
Panagiotis Alexopoulos
  • Function : Author
Alexander Kurz
  • Function : Author
Innocenzo Rainero
  • Function : Author
Elisa Rubino
  • Function : Author
Lorenzo Pinessi
  • Function : Author
Ekaterina Rogaeva
  • Function : Author
Peter St. George-Hyslop
  • Function : Author
Giacomina Rossi
  • Function : Author
Fabrizio Tagliavini
  • Function : Author
Giorgio Giaccone
  • Function : Author
James Rowe
  • Function : Author
Johannes Schlachetzki
  • Function : Author
James Uphill
  • Function : Author
John Collinge
  • Function : Author
Simon Mead
  • Function : Author
Adrian Danek
  • Function : Author
Stuart Pickering-Brown
  • Function : Author
Parastoo Momeni
  • Function : Author
Julie van der Zee
  • Function : Author
Marc Cruts
  • Function : Author
Christine van Broeckhoven
  • Function : Author
Stefano Cappa
  • Function : Author
Didier Hannequin
  • Function : Author
Véronique Golfier
  • Function : Author
Martine Vercelletto
  • Function : Author
Benedetta Nacmias
  • Function : Author
Sandro Sorbi
  • Function : Author
Silvia Bagnoli
  • Function : Author
Irene Piaceri
  • Function : Author
Jørgen Nielsen
  • Function : Author
Lena Hjermind
  • Function : Author
Matthias Riemenschneider
  • Function : Author
Manuel Mayhaus
  • Function : Author
Gilles Gasparoni
  • Function : Author
Sabrina Pichler
  • Function : Author
Bernd Ibach
  • Function : Author
Martin Rossor
  • Function : Author
Nick Fox
  • Function : Author
Jason Warren
  • Function : Author
Maria Grazia Spillantini
  • Function : Author
Huw Morris
  • Function : Author
Patrizia Rizzu
  • Function : Author
Peter Heutink
  • Function : Author
Julie Snowden
  • Function : Author
Sara Rollinson
  • Function : Author
Alexander Gerhard
  • Function : Author
Anna Richardson
  • Function : Author
Amalia Bruni
  • Function : Author
Raffaele Maletta
  • Function : Author
Francesca Frangipane
  • Function : Author
Chiara Cupidi
  • Function : Author
Livia Bernardi
  • Function : Author
Maria Anfossi
  • Function : Author
Maura Gallo
  • Function : Author
Maria Elena Conidi
  • Function : Author
Nicoletta Smirne
  • Function : Author
Rosa Rademakers
  • Function : Author
Matt Baker
  • Function : Author
Dennis Dickson
  • Function : Author
Neill Graff-Radford
  • Function : Author
Ronald Petersen
  • Function : Author
David Knopman
  • Function : Author
Keith Josephs
  • Function : Author
Bradley Boeve
  • Function : Author
Joseph Parisi
  • Function : Author
Bruce Miller
  • Function : Author
Anna Karydas
  • Function : Author
Howard Rosen
  • Function : Author
William Seeley
  • Function : Author
John van Swieten
  • Function : Author
Elise Dopper
  • Function : Author
Harro Seelaar
  • Function : Author
Yolande Pijnenburg
  • Function : Author
Philip Scheltens
  • Function : Author
Giancarlo Logroscino
  • Function : Author
Rosa Capozzo
  • Function : Author
Valeria Novelli
  • Function : Author
Annibale Puca
  • Function : Author
Massimo Franceschi
  • Function : Author
Alfredo Postiglione
  • Function : Author
Graziella Milan
  • Function : Author
Paolo Sorrentino
  • Function : Author
Mark Kristiansen
  • Function : Author
Huei-Hsin Chiang
  • Function : Author
Caroline Graff
  • Function : Author
Florence Pasquier
  • Function : Author
Adeline Rollin
  • Function : Author
Vincent Deramecourt
  • Function : Author
Thibaud Lebouvier
  • Function : Author
Luigi Ferrucci
  • Function : Author
Dimitrios Kapogiannis
  • Function : Author

Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Dates and versions

hal-04556241 , version 1 (23-04-2024)

Identifiers

Cite

Vivek Swarup, Flora Hinz, Jessica Rexach, Ken-Ichi Noguchi, Hiroyoshi Toyoshiba, et al.. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nature Medicine, 2018, 25 (1), pp.152-164. ⟨10.1038/s41591-018-0223-3⟩. ⟨hal-04556241⟩
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