Genome-wide association study and functional validation implicates JADE1 in tauopathy
Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
Grants: MSSM: R01 AG054008, R01 NS095252, R01 AG060961, and R01 NS086736 Tau Consortium, Genentech/Roche, Alexander Saint-Amand Fellowship (JFC), F32 AG056098 and P30 AG066514 (KF), P50 AG005138 and P30 AG066514 (VH, JFC,MS, SG, AG, PH), 75N95019C00049 (VH) K99 AG070109 (SJA) BU / MSSM / MAYO: R01 AG062348 (AM JFC DD) CUMC: P50AG008702 (JPV AFT) BU: U54 NS115266 (AM) UPENN: P30 AG010124, P01 AG017586 and U19 AG062418 (JQT), P30 AG072979 and P01 AG066597 (EBL) 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) 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) Vienna / Toronto: Rossy Foundation and by the Safra Foundation (GGK) MADRC: BT P50 AG05134 (BH) RUSH: ADC grant AG10161 and MAP grant (JS) UCI: R01AG021055 and P50AG016573 (CK) UCSD: P30 AG062429 01 and P50 AG005131 (RR) UK: P30 AG028383 (PN) U Washington: AG05136 AG006781 and the Nancy and Buster Alvord Endowment (DK) Washington U / Knight ADRC: P30 AG066444, P01 AG003991 and P01 AG026276 (DK) Other: J.M.R. Barker Foundation, The McCune Foundation
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