RT Journal Article
SR Electronic
T1 Genome-wide association study and functional validation implicates JADE1 in tauopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.30.450599
DO 10.1101/2021.06.30.450599
A1 Kurt Farrell
A1 SoongHo Kim
A1 Natalia Han
A1 Megan A. Iida
A1 Elias Gonzalez
A1 Marcos Otero-Garcia
A1 Jamie Walker
A1 Tim Richardson
A1 Alan E. Renton
A1 Shea J. Andrews
A1 Brian Fulton-Howard
A1 Jack Humphrey
A1 Ricardo A. Vialle
A1 Kathryn R. Bowles
A1 Kristen Whitney
A1 Diana K. Dangoor
A1 Edoardo Marcora
A1 Marco M. Hefti
A1 Alicia Casella
A1 Cheick Sissoko
A1 Manav Kapoor
A1 Gloriia Novikova
A1 Evan Udine
A1 Garrett Wong
A1 Weijing Tang
A1 Tushar Bhangale
A1 Julie Hunkapiller
A1 Gai Ayalon
A1 Rob Graham
A1 Jonathan D. Cherry
A1 Etty Cortes
A1 Valeriy Borukov
A1 Ann C. McKee
A1 Thor D. Stein
A1 Jean-Paul Vonsattel
A1 Andy F. Teich
A1 Marla Gearing
A1 Jonathan Glass
A1 Juan C. Troncoso
A1 Matthew P. Frosch
A1 Bradley T. Hyman
A1 Dennis W. Dickson
A1 Melissa E. Murray
A1 Johannes Attems
A1 Margaret E. Flanagan
A1 Qinwen Mao
A1 M-Marsel Mesulam
A1 Sandra Weintraub
A1 Randy Woltjer
A1 Thao Pham
A1 Julia Kofler
A1 Julie A. Schneider
A1 Lei Yu
A1 Dushyant P. Purohit
A1 Vahram Haroutunian
A1 Patrick R. Hof
A1 Sam Gandy
A1 Mary Sano
A1 Thomas G. Beach
A1 Wayne Poon
A1 Claudia Kawas
A1 María Corrada
A1 Robert A. Rissman
A1 Jeff Metcalf
A1 Sara Shuldberg
A1 Bahar Salehi
A1 Peter T. Nelson
A1 John Q. Trojanowski
A1 Edward B. Lee
A1 David A. Wolk
A1 Corey T. McMillan
A1 Dirk C. Keene
A1 Thomas J. Montine
A1 Gabor G. Kovacs
A1 Mirjam I. Lutz
A1 Peter Fischer
A1 Richard J. Perrin
A1 Nigel Cairns
A1 Erin E. Franklin
A1 Herbert T. Cohen
A1 Maria Inmaculada Cobos Sillero
A1 Bess Frost
A1 Towfique Raj
A1 Alison Goate
A1 Charles L. White III
A1 John F. Crary
YR 2021
UL http://biorxiv.org/content/early/2021/07/01/2021.06.30.450599.abstract
AB Primary 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.Competing Interest StatementThe authors have declared no competing interest.