Journal article
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Nature medicine, Vol.25(1), pp.152-164
01/01/2019
DOI: 10.1038/s41591-018-0223-3
PMCID: PMC6602064
PMID: 30510257
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.
Details
- Title: Subtitle
- Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
- Creators
- Vivek Swarup - University of California, Los AngelesFlora I. Hinz - University of California, Los AngelesJessica E. Rexach - University of California, Los AngelesKen-ichi Noguchi - Takeda (Japan)Hiroyoshi Toyoshiba - Takeda (Japan)Akira Oda - Takeda (Japan)Keisuke Hirai - Takeda (Japan)Nicholas T. Seyfried - Emory UniversityChialin Cheng - MIT, Ctr Genom Med, Chem Neurobiol Lab, Boston, MA USAStephen J. Haggarty - Massachusetts General HospitalRaffaele Ferrari - UCL, Dept Mol Neurosci, London, EnglandJonathan D. Rohrer - UCL, Dept Mol Neurosci, London, EnglandAdaikalavan Ramasamy - UCL, Dept Mol Neurosci, London, EnglandJohn Hardy - UCL, Dept Mol Neurosci, London, EnglandDena G. Hernandez - NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USAMichael A. Nalls - NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USAAndrew B. Singleton - NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USAJohn B. J. Kwok - Neurosci Res Australia, Sydney, NSW, AustraliaCarol Dobson-Stone - Neurosci Res Australia, Sydney, NSW, AustraliaWilliam S. Brooks - Neurosci Res Australia, Sydney, NSW, AustraliaPeter R. Schofield - Neurosci Res Australia, Sydney, NSW, AustraliaGlenda M. Halliday - Neurosci Res Australia, Sydney, NSW, AustraliaJohn R. Hodges - Neurosci Res Australia, Sydney, NSW, AustraliaOlivier Piguet - Neurosci Res Australia, Sydney, NSW, AustraliaLauren Bartley - Neurosci Res Australia, Sydney, NSW, AustraliaElizabeth Thompson - Womens & Childrens Hosp, South Australian Clin Genet Serv, Adelaide, SA, AustraliaEric Haan - Womens & Childrens Hosp, South Australian Clin Genet Serv, Adelaide, SA, AustraliaIsabel Hernandez - Fundació ACEAgustin Ruiz - Fundació ACEMerce Boada - Fundació ACEBarbara Borroni - University of BresciaAlessandro Padovani - University of BresciaNigel J. Cairns - Washington Univ, Sch Med, Hope Ctr, St Louis, MO USACarlos Cruchaga - Washington Univ, Sch Med, Hope Ctr, St Louis, MO USAGiuliano Binetti - FatebenefratelliRoberta Ghidoni - FatebenefratelliLuisa Benussi - FatebenefratelliGianluigi Forloni - Ist Ric Farmacol, IRCCS, Biol Neurodegenerat Disorders, Milan, ItalyDiego Albani - Mylan (Switzerland)Daniela Galimberti - University of MilanChiara Fenoglio - University of MilanMaria Serpente - University of MilanElio Scarpini - University of MilanJordi Clarimon - Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Neurol Dept, Memory Unit, Barcelona, SpainAlberto Lleo - Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Neurol Dept, Memory Unit, Barcelona, SpainRafael Blesa - Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Neurol Dept, Memory Unit, Barcelona, SpainMaria Landqvist Waldo - Lund UniversityKarin Nilsson - Lund UniversityChrister Nilsson - Lund UniversityIan R. A. Mackenzie - University of British ColumbiaGing-Yuek R. Hsiung - University of British ColumbiaDavid M. A. Mann - University of ManchesterJordan Grafman - Northwestern UniversityChristopher M. Morris - Newcastle Univ, Inst Ageing, Newcastle Upon Tyne, Tyne & Wear, EnglandJohannes Attems - University of Newcastle AustraliaTimothy D. Griffiths - Newcastle Univ, Inst Ageing, Newcastle Upon Tyne, Tyne & Wear, EnglandIan G. McKeith - Newcastle Univ, Inst Ageing, Newcastle Upon Tyne, Tyne & Wear, EnglandAlan J. Thomas - Newcastle UniversityEvelyn Jaros - Newcastle UniversityPietro Pietrini - IMT Sch Adv Studies, Lucca, ItalyEdward D. Huey - Columbia UniversityEric M. Wassermann - NINDS, Behav Neurol Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USAMichael C. Tierney - NINDS, Behav Neurol Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USAAtik Baborie - University of AlbertaPau Pastor - Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, SpainSara Ortega-Cubero - Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, SpainCristina Razquin - Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, Pamplona, SpainElena Alonso - Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, Pamplona, SpainRobert Perneczky - Imperial Coll Sci Technol & Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, EnglandJanine Diehl-Schmid - Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, GermanyPanagiotis Alexopoulos - Ludwig-Maximilians-Universität MünchenAlexander Kurz - Ludwig-Maximilians-Universität MünchenInnocenzo Rainero - Univ Torino, Dept Neurosci, Turin, ItalyElisa Rubino - Univ Torino, Dept Neurosci, Turin, ItalyLorenzo Pinessi - Univ Torino, Dept Neurosci, Turin, ItalyEkaterina Rogaeva - University of TorontoPeter St George-Hyslop - University of TorontoGiacomina Rossi - Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, ItalyFabrizio Tagliavini - Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, ItalyGiorgio Giaccone - Mylan (Switzerland)James B. Rowe - University of CambridgeJohannes C. M. Schlachetzki - Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USAJames Uphill - MRC Prion UnitJohn Collinge - MRC Prion UnitSimon Mead - MRC Prion UnitAdrian Danek - Ludwig Maximilians Univ Munchen, Neurol Klin & Poliklin, Munich, GermanyVivianna M. Van Deerlin - University of PennsylvaniaMurray Grossman - University of PennsylvaniaJohn Q. Trojanowski - University of PennsylvaniaStuart Pickering-Brown - University of ManchesterParastoo Momeni - Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Lab Neurogenet, Lubbock, TX 79430 USAJulie van der Zee - VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, BelgiumMarc Cruts - VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, BelgiumChristine Van Broeckhoven - VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, BelgiumStefano F. Cappa - Mylan (Switzerland)Isabelle Leber - InsermAlexis Brice - InsermDidier Hannequin - Rouen Univ Hosp, Serv Neurol, Rouen, FranceVeronique Golfier - Serv Neurol, St Brieuc, FranceMartine Vercelletto - Charmo UniversityBenedetta Nacmias - University of FlorenceSandro Sorbi - University of FlorenceSilvia Bagnoli - University of FlorenceIrene Piaceri - University of FlorenceJorgen E. Nielsen - Copenhagen Univ Hosp, Rigshosp, Dept Neurol, Danish Dementia Res Ctr,Neurogenet Clin, Copenhagen, DenmarkLena E. Hjermind - Copenhagen Univ Hosp, Rigshosp, Dept Neurol, Danish Dementia Res Ctr,Neurogenet Clin, Copenhagen, DenmarkMatthias Riemenschneider - Saarland UniversityManuel Mayhaus - Saarland UniversityGilles Gasparoni - Saarland UniversitySabrina Pichler - Saarland UniversityBernd Ibach - University of RegensburgMartin N. Rossor - UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, EnglandNick C. Fox - UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, EnglandJason D. Warren - UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, EnglandMaria Grazia Spillantini - University of CambridgeHuw R. Morris - UCL, Dept Mol Neurosci, London, EnglandPatrizia Rizzu - German Ctr Neurodegenerat Diseases Tubingen, Tubingen, GermanyPeter Heutink - German Ctr Neurodegenerat Diseases Tubingen, Tubingen, GermanyJulie S. Snowden - University of ManchesterAlexander Gerhard - University of ManchesterSara Rollinson - University of ManchesterAnna Richardson - University of ManchesterAmalia C. Bruni - University of ManchesterRaffaele Maletta - University of ManchesterFrancesca Frangipane - University of ManchesterChiara Cupidi - University of ManchesterLivia Bernardi - University of ManchesterMaria Anfossi - University of ManchesterMaura Gallo - ASPCZ, Reg Neurogenet Ctr, Lamezia Terme, ItalyMaria Elena Conidi - ASPCZ, Reg Neurogenet Ctr, Lamezia Terme, ItalyNicoletta Smirne - ASPCZ, Reg Neurogenet Ctr, Lamezia Terme, ItalyRosa Rademakers - Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USAMatt Baker - Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USADennis W. Dickson - Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USANeill R. Graff-Radford - Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USARonald C. Petersen - Mayo Clin Rochester, Dept Neurol, Rochester, MN USADavid Knopman - Mayo Clin Rochester, Dept Neurol, Rochester, MN USAKeith A. Josephs - Mayo Clin Rochester, Dept Neurol, Rochester, MN USABradley F. Boeve - Mayo Clin Rochester, Dept Neurol, Rochester, MN USAJoseph E. Parisi - Mayo Clin Rochester, Dept Pathol, Rochester, MN USABruce L. Miller - Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USAAnna M. Karydas - Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USAHoward Rosen - Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USAWilliam W. Seeley - Univ Calif San Francisco, Dept Neurol, San Francisco, CA USAJohn C. van Swieten - Erasmus MCElise G. P. Dopper - Erasmus MCHarro Seelaar - Erasmus MCYolande A. L. Pijnenburg - University of AmsterdamPhilip Scheltens - University of AmsterdamGiancarlo Logroscino - University of Bari Aldo MoroRosa Capozzo - University of Bari Aldo MoroValeria Novelli - Fdn Policlin Univ Agostino Gemelli, Med Genet Unit, Rome, ItalyAnnibale A. Puca - Mylan (Switzerland)Massimo Franceschi - Mylan (Switzerland)Alfredo Postiglione - University of Naples Federico IIGraziella Milan - ASL Napoli 1 Ctr, Geriatr Ctr Frullone, Naples, ItalyPaolo Sorrentino - ASL Napoli 1 Ctr, Geriatr Ctr Frullone, Naples, ItalyMark Kristiansen - UCL, ICH, UCL Genom, London, EnglandHuei-Hsin Chiang - Karolinska InstitutetCaroline Graff - Karolinska InstitutetFlorence Pasquier - Université de LilleAdeline Rollin - Université de LilleVincent Deramecourt - Université de LilleThibaud Lebouvier - Univ Lille, Lille, FranceLuigi Ferrucci - NIA, Clin Res Branch, Baltimore, MD 21224 USADimitrios Kapogiannis - NIA, Cellular & Mol Neurosci Sect, Baltimore, MD 21224 USAJames J. Lah - Emory UniversityAllan I. Levey - Emory UniversityShinichi Kondou - Takeda (Japan)Daniel H. Geschwind - University of California, Los AngelesInternational Frontotemporal Dementia Genomics Consortium
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.25(1), pp.152-164
- DOI
- 10.1038/s41591-018-0223-3
- PMID
- 30510257
- PMCID
- PMC6602064
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Publisher
- Springer Nature
- Number of pages
- 18
- Grant note
- Larry L. Hillblom Foundation Postdoctoral Fellowship R25NS065723 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Michael J. Fox Foundation for Parkinson's Research P50 AG016574; R01 AG032990; U01 AG046139; R01 AG018023; U01 AG006576; U01 AG006786; R01 AG025711; R01 AG017216; R01 AG003949 / National Institute on Aging (NIA); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01 NS080820 / National Institute of Neurological Disorders and Stroke (NINDS); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Takeda Pharmaceuticals; Takeda Pharmaceutical Company Ltd CurePSP Foundation P30 AG19610 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) 211002 / Arizona Department of Health Services Rainwater Charitable Foundation/Tau consortium U24 NS072026 / NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 4001; 0011; 05-901; 1001 / Arizona Biomedical Research Commission Mayo Foundation P50AG005681 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) G0400074 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 5R25 NS065723; 5U01AG046161 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 01/01/2019
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627315902771
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