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.

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Data availability

miRNA-seq and mRNA-seq data from TPR50 tau mice, microarray data on PS19 hippocampus, microarray data on overexpression of miR-203 in vitro, RNA-seq on sorted mouse neurons and RNA-seq data with SAHA are available from the NCBI Gene Expression Omnibus database under Gene Expression Omnibus accession number GSE90696. Human FTD miRNA-seq and mRNA-seq data are available from https://www.synapse.org/#!Synapse:syn7818788. Human UPenn FTD Proteomics data are available from https://www.synapse.org/#!Synapse:syn9884357. The custom code used for the analysis can be accessed using this link in github: https://github.com/dhglab/Identification-of-evolutionarily-conserved-gene-networks-mediating-neurodegenerative-dementia

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


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Funding for this work was provided by Takeda Pharmaceuticals (D.H.G.), Rainwater Charitable Foundation/Tau consortium (D.H.G., S.J.H.), NIH grants to D.H.G., S.J.H., A.L. (5U01AG046161) and J.R. (5R25 NS065723) and Larry L. Hillblom Foundation Postdoctoral Fellowship to V.S. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceuticals. The authors thank M. Hattori, Y. Obayashi and K. Nakamura for their contribution to the TPR50 mouse sample preparation and analysis. The authors thank M. Gearing at the Emory Alzheimer’s Disease Research Center brain bank for providing human FTD samples. The authors also thank N. Parikshak for help with network analysis and critical reading of the manuscript. We thank Eli Lilly and Company scientists for generating the Tg4510 microglia RNA-seq data and providing access to them. For the PSP and FTD temporal cortex RNA-seq dataset, study data were provided by the following sources: Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Taner and S. G. Younkin, Mayo Clinic Jacksonville, using samples from the Mayo Clinic Study of Aging, Mayo Clinic Alzheimer’s Disease Research Center, and Mayo Clinic Brain Bank. Data collection was supported through funding by National Institute on Aging (NIA) grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Tg4510 replication and CRND8 RNA-seq data were provided by the NIH U01 AG046139. We thank J. Lewis, K. Duff, D. Westaway and D. Borchelt for generating these lines of transgenic mice and providing access to them.

Author information

Author notes

  1. These authors contributed equally to this work: Vivek Swarup, Flora I. Hinz.

  2. A full list of members and affiliations appears at the end of this paper.


  1. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Vivek Swarup
    • , Flora I. Hinz
    • , Jessica E. Rexach
    • , Arjun Sarkar
    •  & Daniel H. Geschwind
  2. CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan

    • Ken-ichi Noguchi
    • , Hiroyoshi Toyoshiba
    • , Akira Oda
    • , Keisuke Hirai
    •  & Shinichi Kondou
  3. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

    • Nicholas T. Seyfried
  4. Alzheimer’s Disease Research Center and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    • Nicholas T. Seyfried
    • , James J. Lah
    •  & Allan I. Levey
  5. Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Chialin Cheng
    •  & Stephen J. Haggarty
  6. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    • Murray Grossman
    •  & Murray Grossman
  7. The Penn FTD Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    • Vivianna M. Van Deerlin
    • , John Q. Trojanowski
    • , Vivianna M. Van Deerlin
    •  & John Q. Trojanowski
  8. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Daniel H. Geschwind
  9. Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA

    • Daniel H. Geschwind
  10. Department of Molecular Neuroscience, University College London (UCL), London, UK

    • Raffaele Ferrari
    • , Jonathan D. Rohrer
    • , Adaikalavan Ramasamy
    •  & John Hardy
  11. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    • Dena G. Hernandez
    • , Michael A. Nalls
    •  & Andrew B. Singleton
  12. Neuroscience Research Australia, Sydney, New South Wales, Australia

    • John B. J. Kwok
    • , Carol Dobson-Stone
    • , William S. Brooks
    • , Peter R. Schofield
    • , Glenda M. Halliday
    • , John R. Hodges
    • , Olivier Piguet
    •  & Lauren Bartley
  13. South Australian Clinical Genetics Service, Women’s and Children’s Hospital, Adelaide, South Australia, Australia

    • Elizabeth Thompson
    •  & Eric Haan
  14. Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

    • Isabel Hernández
    • , Agustín Ruiz
    •  & Mercè Boada
  15. Neurology Clinic, University of Brescia, Brescia, Italy

    • Barbara Borroni
    •  & Alessandro Padovani
  16. Hope Center, Washington University School of Medicine, St. Louis, MO, USA

    • Nigel J. Cairns
    •  & Carlos Cruchaga
  17. IRCCS Istituto Centro San Giovanni di Dio – Fatebenefratelli, Brescia, Italy

    • Giuliano Binetti
    • , Roberta Ghidoni
    •  & Luisa Benussi
  18. Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche, Milan, Italy

    • Gianluigi Forloni
    •  & Diego Albani
  19. University of Milan, Milan, Italy

    • Daniela Galimberti
    • , Chiara Fenoglio
    • , Maria Serpente
    •  & Elio Scarpini
  20. Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy

    • Daniela Galimberti
    • , Chiara Fenoglio
    • , Maria Serpente
    •  & Elio Scarpini
  21. Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    • Jordi Clarimón
    • , Alberto Lleó
    •  & Rafael Blesa
  22. Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden

    • Maria Landqvist Waldö
    • , Karin Nilsson
    •  & Christer Nilsson
  23. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

    • Ian R. A. Mackenzie
    •  & Ging-Yuek R. Hsiung
  24. Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK

    • David M. A. Mann
  25. Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology and the Alzheimer’s Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    • Jordan Grafman
  26. Institute for Ageing, Newcastle University, Newcastle-upon-Tyne, UK

    • Christopher M. Morris
    • , Johannes Attems
    • , Timothy D. Griffiths
    • , Ian G. McKeith
    • , Alan J. Thomas
    •  & Evelyn Jaros
  27. IMT School for Advanced Studies, Lucca, Lucca, Italy

    • Pietro Pietrini
  28. Taub Institute, Departments of Psychiatry and Neurology, Columbia University, New York, NY, USA

    • Edward D. Huey
  29. Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, Bethesda, MD, USA

    • Eric M. Wassermann
    •  & Michael C. Tierney
  30. Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada

    • Atik Baborie
  31. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    • Pau Pastor
    •  & Sara Ortega-Cubero
  32. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    • Cristina Razquin
    •  & Elena Alonso
  33. Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College of Science, Technology and Medicine, London, UK

    • Robert Perneczky
  34. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany

    • Janine Diehl-Schmid
    • , Panagiotis Alexopoulos
    •  & Alexander Kurz
  35. Department of Neuroscience, University of Torino, Turin, Italy

    • Innocenzo Rainero
    • , Elisa Rubino
    •  & Lorenzo Pinessi
  36. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada

    • Ekaterina Rogaeva
    •  & Peter St. George-Hyslop
  37. Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    • Giacomina Rossi
    • , Fabrizio Tagliavini
    •  & Giorgio Giaccone
  38. Cambridge University Department of Clinical Neurosciences, Cambridge, UK

    • James B. Rowe
  39. Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA

    • Johannes C. M. Schlachetzki
  40. MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    • James Uphill
    • , John Collinge
    •  & Simon Mead
  41. Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany

    • Adrian Danek
  42. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    • Stuart Pickering-Brown
  43. Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA

    • Parastoo Momeni
  44. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium

    • Julie van der Zee
    • , Marc Cruts
    •  & Christine Van Broeckhoven
  45. Neurorehabilitation Unit, Department of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy

    • Stefano F. Cappa
  46. Inserm, CRICM, Paris, France

    • Isabelle Leber
    •  & Alexis Brice
  47. Service de Neurologie, Rouen University Hospital, Rouen, France

    • Didier Hannequin
  48. Service de Neurologie, CH, Saint-Brieuc, France

    • Véronique Golfier
  49. Service de Neurologie, CHU, Nantes, France

    • Martine Vercelletto
  50. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy

    • Benedetta Nacmias
    • , Sandro Sorbi
    • , Silvia Bagnoli
    •  & Irene Piaceri
  51. Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    • Jørgen E. Nielsen
    •  & Lena E. Hjermind
  52. Saarland University Hospital, Laboratory for Neurogenetics, Homburg (Saar), Germany

    • Matthias Riemenschneider
    • , Manuel Mayhaus
    • , Gilles Gasparoni
    •  & Sabrina Pichler
  53. Department of Psychiatry, Psychotherapy and Psychosomatics, University Regensburg, Regensburg, Germany

    • Bernd Ibach
  54. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    • Martin N. Rossor
    • , Nick C. Fox
    •  & Jason D. Warren
  55. Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, University of Cambridge, Cambridge, UK

    • Maria Grazia Spillantini
  56. Department of Molecular Neuroscience, UCL, London, UK

    • Huw R. Morris
  57. German Center for Neurodegenerative Diseases-Tübingen, Tübingen, Germany

    • Patrizia Rizzu
    •  & Peter Heutink
  58. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    • Julie S. Snowden
    • , Sara Rollinson
    •  & Alexander Gerhard
  59. Salford Royal Foundation Trust, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    • Anna Richardson
    • , Amalia C. Bruni
    • , Raffaele Maletta
    • , Francesca Frangipane
    • , Chiara Cupidi
    • , Livia Bernardi
    •  & Maria Anfossi
  60. Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy

    • Maura Gallo
    • , Maria Elena Conidi
    •  & Nicoletta Smirne
  61. Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA

    • Rosa Rademakers
    • , Matt Baker
    • , Dennis W. Dickson
    •  & Neill R. Graff-Radford
  62. Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA

    • Ronald C. Petersen
    • , David Knopman
    • , Keith A. Josephs
    •  & Bradley F. Boeve
  63. Department of Pathology, Mayo Clinic Rochester, Rochester, MN, USA

    • Joseph E. Parisi
  64. Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA

    • Bruce L. Miller
    • , Anna M. Karydas
    •  & Howard Rosen
  65. Department of Neurology, University of California, San Francisco, CA, USA

    • William W. Seeley
  66. Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands

    • John C. van Swieten
    • , Elise G. P. Dopper
    •  & Harro Seelaar
  67. Alzheimer Centre and Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands

    • Yolande A. L. Pijnenburg
    •  & Philip Scheltens
  68. Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    • Giancarlo Logroscino
    •  & Rosa Capozzo
  69. Medical Genetics Unit, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy

    • Valeria Novelli
  70. Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy

    • Annibale A. Puca
  71. Department of Medicine and Surgery, University of Salerno, Baronissi, Italy

    • Annibale A. Puca
  72. Neurology Department, IRCCS Multimedica, Milan, Italy

    • Massimo Franceschi
  73. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    • Alfredo Postiglione
  74. Geriatric Center Frullone-ASL Napoli 1 Centro, Naples, Italy

    • Graziella Milan
    •  & Paolo Sorrentino
  75. UCL Genomics, Institute of Child Health (ICH), UCL, London, UK

    • Mark Kristiansen
  76. Department NVS, Alzheimer Research Center, Karolinska Institutet, Novum, Stockholm, Sweden

    • Huei-Hsin Chiang
    •  & Caroline Graff
  77. University of Lille, Lille, France

    • Florence Pasquier
    • , Adeline Rollin
    • , Vincent Deramecourt
    •  & Thibaud Lebouvier
  78. Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA

    • Luigi Ferrucci
  79. Cellular and Molecular Neuroscience Section, National Institute on Aging, Baltimore, MD, USA

    • Dimitrios Kapogiannis


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  1. International Frontotemporal Dementia Genomics Consortium


V.S. and D.H.G. planned and directed the experiments, guided the analysis and wrote the manuscript in conjunction with F.I.H. and J.E.R. All authors revised and edited the final version of the manuscript. F.I.H. performed all the experiments in mouse cortical cultures. V.S. performed all the bioinformatic analyses and performed dissections on human postmortem samples and isolated RNA. K.N., H.T., A.O., K.H. and S.K. bred the TPR50 mouse, characterized the F1 hybrids and collected the tissue samples. J.E.R. performed bioinformatic analysis using purified glial cells. J.E.R. and A.S. stained for and quantified inflammation in mouse brain samples. IFGC consortia members collected and analyzed FTD GWAS data. N.T.S., J.J.L. and A.I.L. performed mass spectrometry–based quantitative proteomics on human FTD samples obtained from M.G., V.M.V.D. and J.Q.T. The SAHA experiments were performed by C.C. and S.J.H. on human iPSC-derived neurons from tau and control patients.

Competing interests

D.H.G. has received research funding from Takeda Pharmaceutical Company Limited. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceutical Company Limited.

Corresponding author

Correspondence to Daniel H. Geschwind.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–10

  2. Reporting Summary

  3. Supplementary Table 1

    TPR50 mRNA-seq Analysis

  4. Supplementary Table 2

    Human transcriptomics and proteomics data

  5. Supplementary Table 3

    TPR50 miRNA-seq analysis

  6. Supplementary Table 4

    Module preservation and connectivity map

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