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

Kurt Farrell, Soong Ho Kim, Natalia Han, Megan A. Iida, Elias M. Gonzalez, Marcos Otero-Garcia, Jamie M. Walker, Timothy E. Richardson, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Katia de Paiva Lopes, Kristen Whitney, Diana K. Dangoor, Hadley Walsh, Edoardo Marcora, Marco M. HeftiAlicia Casella, Cheick T. Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Robert R. Graham, Jonathan D. Cherry, Etty P. Cortes, Valeriy Y. Borukov, Ann C. McKee, Thor D. Stein, Jean Paul Vonsattel, Andy F. Teich, Marla Gearing, Jonathan Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Dennis W. Dickson, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M. Marsel Mesulam, Sandra Weintraub, Randy L. Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne Poon, Claudia H. Kawas, María M. Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, C. Dirk Keene, Caitlin S. Latimer, Thomas J. Montine, Gabor G. Kovacs, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel J. Cairns, Erin E. Franklin, Herbert T. Cohen, Towfique Raj, Inma Cobos, Bess Frost, Alison Goate, Charles L. White, John F. Crary

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)33-53
Number of pages21
JournalActa Neuropathologica
Volume143
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

Funding Information:
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 Information:
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.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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