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

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

ASJC Scopus subject areas

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

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