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Genome-wide association study and functional validation implicates JADE1 in tauopathy

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Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

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Acknowledgements

The authors would like to acknowledge the neuropathology core of the Massachusetts Alzheimer Disease Research Center, the Biosample Management Repository at Genentech/Roche, the brain repository at UCI, Knight Alzheimer Disease Research Center Neuropathology Core at Washington University School of Medicine, the BioRepository and Integrated Neuropathology Laboratory and Precision Neuropathology Core at the University of Washington, the neurodegenerative disease brain bank at the University of California San Francisco, the Neuropathology Brain Bank & Research Core at Mount Sinai, the Newcastle Brain Tissue Resource, and the following people: Ryan Cassidy Bohannan, Chad Caraway, Allison Beller, Kim Howard, Suresh Selvaraj, Ward Ortmann, Ping Shang, Jeff Harris, and Chan Foong. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org).

Funding

IMSSM: R01 AG054008, R01 NS095252, R01 AG060961, and R01 NS086736 Rainwater Charitable Foundation, Genentech/Roche, Alexander Saint-Amand Fellowship (JFC), F32 AG056098 and P30 AG066514 (KF), P50 AG005138 and P30 AG066514 (VH, JFC, MS, SG, AG, PRH), 75N95019C00049 (VH), K99 AG070109 (SJA), U01 AG058635 (AG, EM, AER) BU / MSSM / MAYO: R01 AG062348 (AM JFC DD), UMC: P50AG008702 (JPV AFT), BU: U54 NS115266 (AM), R01 CA079830 (HTC), UPENN: P30 AG010124, P01 AG017586 and U19 AG062418 (JQT), P30 AG072979 and P01 AG066597 (EBL), R01 AG066152 (CTM), PITT: R01 AG066152 P30 AG066468 (JK), Banner: U24 NS072026 and P30 AG019610 The Arizona Department of Health Services, and the Michael J. Fox Foundation for Parkinson’s Research (TB), Johns Hopkins: P50 AG05146 (JCT), U Iowa: K23 NS109284, The Roy J. Carver Foundation, the Carver College of Medicine, and the Williams-Cannon Foundation (MMH), Northwestern: P30 AG013854 (MEF), Emory: P30 NS055077 and P50 AG025688 (MG), OHSU: P30 AG08017 (RW), UTSW: Winspear Family Center for Research on the Neuropathology of Alzheimer Disease (CWIII), Toronto: Rossy Foundation and by the Safra Foundation (GGK), Stanford: R01AG059848 (IC), MADRC: P50 AG05134, P30 AG062421 (BTH), RUSH: ADC grant AG10161 and MAP grant (JS), UCI: R01AG021055 and P50AG016573 (CHK, MMC), P01AG000538 (WP), UCSD: P30 AG062429 01 and P50 AG005131 (RR), UK: P30 AG028383 (PN), U Washington: P50 AG005136, P30 AG066509, U01 AG006781, U19 066567 and the Nancy and Buster Alvord Endowment (CDK), Washington U / Knight ADRC: P30 AG066444, P01 AG003991, 01 AG026276 (RJP), Newcastle: UK Medical Research Council (G0400074), by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK and by the NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (JA), Other: J.M.R. Barker Foundation, The McCune Foundation.

Author information

Authors and Affiliations

  1. Department of Pathology, Neuropathology Brain Bank and Research CoRE, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1194, New York, NY, 10029, USA

    Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Kristen Whitney, Diana K. Dangoor, Hadley Walsh, Alicia Casella, Cheick T. Sissoko, Etty P. Cortes, Valeriy Y. Borukov, Dushyant P. Purohit & John F. Crary

  2. Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Katia de Paiva Lopes, Kristen Whitney, Diana K. Dangoor, Hadley Walsh, Edoardo Marcora, Alicia Casella, Cheick T. Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Etty P. Cortes, Valeriy Y. Borukov, Vahram Haroutunian, Patrick R. Hof, Towfique Raj, Alison Goate & John F. Crary

  3. Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kurt Farrell, SoongHo Kim, Natalia Han, Megan A. Iida, Kristen Whitney, Diana K. Dangoor, Hadley Walsh, Alicia Casella, Cheick T. Sissoko & John F. Crary

  4. Department of Cell Systems and Anatomy, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA

    Elias M. Gonzalez & Bess Frost

  5. Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, USA

    Marcos Otero-Garcia

  6. Department of Pathology and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA

    Jamie M. Walker & Timothy E. Richardson

  7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Katia de Paiva Lopes, Edoardo Marcora, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Towfique Raj & Alison Goate

  8. Department of Pathology, University of Iowa, Iowa City, IA, USA

    Marco M. Hefti

  9. Department of Human Genetics, Genentech, South San Francisco, CA, USA

    Tushar Bhangale & Julie Hunkapiller

  10. Neumora Therapeutics, South San Francisco, CA, USA

    Gai Ayalon

  11. Maze Therapeutics, San Francisco, CA, USA

    Robert R. Graham

  12. Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Cherry, Ann C. McKee & Thor D. Stein

  13. Department of Pathology and Cell Biology, Department of Neurology, and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Jean-Paul Vonsattel & Andy F. Teich

  14. Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA

    Marla Gearing & Jonathan Glass

  15. Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Juan C. Troncoso

  16. Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA

    Matthew P. Frosch & Bradley T. Hyman

  17. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Dennis W. Dickson & Melissa E. Murray

  18. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Johannes Attems

  19. Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Margaret E. Flanagan, Qinwen Mao, M.-Marsel Mesulam & Sandra Weintraub

  20. Department of Pathology, Oregon Health Sciences University, Portland, OR, USA

    Randy L. Woltjer & Thao Pham

  21. Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Julia Kofler

  22. Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    Julie A. Schneider & Lei Yu

  23. Department of Psychiatry, Alzheimer’s Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Dushyant P. Purohit, Vahram Haroutunian, Sam Gandy & Mary Sano

  24. Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA

    Thomas G. Beach

  25. Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA

    Wayne Poon & María M. Corrada

  26. Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA

    Robert A. Rissman, Jeff Metcalf, Sara Shuldberg & Bahar Salehi

  27. Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Peter T. Nelson

  28. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    John Q. Trojanowski & Edward B. Lee

  29. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    David A. Wolk & Corey T. McMillan

  30. Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA

    C. Dirk Keene, Caitlin S. Latimer & Thomas J. Montine

  31. Department of Pathology, Stanford University, Palo Alto, USA

    Weijing Tang, Thomas J. Montine & Inma Cobos

  32. Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada

    Gabor G. Kovacs

  33. Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Gabor G. Kovacs

  34. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Gabor G. Kovacs & Mirjam I. Lutz

  35. Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Richard J. Perrin & Erin E. Franklin

  36. Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA

    Herbert T. Cohen

  37. Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, USA

    Charles L. White III

  38. College of Medicine and Health, University of Exeter, Exeter, UK

    Nigel J. Cairns

  39. Department of Neurology, Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Sam Gandy

  40. Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA

    Claudia H. Kawas

  41. Department of Psychiatry, Danube Hospital, Vienna, Austria

    Peter Fischer

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 JFC, DWD, MF, PRH, GGK, EBL, PTN, JQT, are editorial board members and JA is editor in chief of Acta Neuropathologica, but were not involved in the editorial handling of this article. JH, TB, are employees of Genentech (a subsidiary of Roche) and hold stocks/stock options in FH-LR Ltd. AG is on the Scientific advisory board for Genentech and consultant for AbbVie. All other authors declare no relevant conflicts.

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Farrell, K., Kim, S., Han, N. et al. Genome-wide association study and functional validation implicates JADE1 in tauopathy. Acta Neuropathol 143, 33–53 (2022). https://doi.org/10.1007/s00401-021-02379-z

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