Author:
Farrell Kurt,Kim SoongHo,Han Natalia,Iida Megan A.,Gonzalez Elias,Otero-Garcia Marcos,Walker Jamie,Richardson Tim,Renton Alan E.,Andrews Shea J.,Fulton-Howard Brian,Humphrey Jack,Vialle Ricardo A.,Bowles Kathryn R.,Whitney Kristen,Dangoor Diana K.,Marcora Edoardo,Hefti Marco M.,Casella Alicia,Sissoko Cheick,Kapoor Manav,Novikova Gloriia,Udine Evan,Wong Garrett,Tang Weijing,Bhangale Tushar,Hunkapiller Julie,Ayalon Gai,Graham Rob,Cherry Jonathan D.,Cortes Etty,Borukov Valeriy,McKee Ann C.,Stein Thor D.,Vonsattel Jean-Paul,Teich Andy F.,Gearing Marla,Glass Jonathan,Troncoso Juan C.,Frosch Matthew P.,Hyman Bradley T.,Dickson Dennis W.,Murray Melissa E.,Attems Johannes,Flanagan Margaret E.,Mao Qinwen,Mesulam M-Marsel,Weintraub Sandra,Woltjer Randy,Pham Thao,Kofler Julia,Schneider Julie A.,Yu Lei,Purohit Dushyant P.,Haroutunian Vahram,Hof Patrick R.,Gandy Sam,Sano Mary,Beach Thomas G.,Poon Wayne,Kawas Claudia,Corrada María,Rissman Robert A.,Metcalf Jeff,Shuldberg Sara,Salehi Bahar,Nelson Peter T.,Trojanowski John Q.,Lee Edward B.,Wolk David A.,McMillan Corey T.,Keene Dirk C.,Montine Thomas J.,Kovacs Gabor G.,Lutz Mirjam I.,Fischer Peter,Perrin Richard J.,Cairns Nigel,Franklin Erin E.,Cohen Herbert T.,Cobos Sillero Maria Inmaculada,Frost Bess,Raj Towfique,Goate Alison,White Charles L.,Crary John F.
Abstract
AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy 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) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as 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 adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, 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 brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. 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 mediator of neurofibrillary degeneration.
Publisher
Cold Spring Harbor Laboratory