Journal article
Genome-wide association study and functional validation implicates JADE1 in tauopathy
Acta neuropathologica, Vol.143(1), pp.33-53
11/01/2021
DOI: 10.1007/s00401-021-02379-z
PMCID: PMC8786260
PMID: 34719765
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.
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Details
- Title: Subtitle
- Genome-wide association study and functional validation implicates JADE1 in tauopathy
- Creators
- Kurt FarrellSoongHo KimNatalia HanMegan A IidaElias M GonzalezMarcos Otero-GarciaJamie M WalkerTimothy E RichardsonAlan E RentonShea J AndrewsBrian Fulton-HowardJack HumphreyRicardo A VialleKathryn R BowlesKatia de Paiva LopesKristen WhitneyDiana K DangoorHadley WalshEdoardo MarcoraMarco M HeftiAlicia CasellaCheick T SissokoManav KapoorGloriia NovikovaEvan UdineGarrett WongWeijing TangTushar BhangaleJulie HunkapillerGai AyalonRobert R GrahamJonathan D CherryEtty P CortesValeriy Y BorukovAnn C McKeeThor D SteinJean-Paul VonsattelAndy F TeichMarla GearingJonathan GlassJuan C TroncosoMatthew P FroschBradley T HymanDennis W DicksonMelissa E MurrayJohannes AttemsMargaret E FlanaganQinwen MaoM.-Marsel MesulamSandra WeintraubRandy L WoltjerThao PhamJulia KoflerJulie A SchneiderLei YuDushyant P PurohitVahram HaroutunianPatrick R HofSam GandyMary SanoThomas G BeachWayne PoonClaudia H KawasMaría M CorradaRobert A RissmanJeff MetcalfSara ShuldbergBahar SalehiPeter T NelsonJohn Q TrojanowskiEdward B LeeDavid A WolkCorey T McMillanC. Dirk KeeneCaitlin S LatimerThomas J MontineGabor G KovacsMirjam I LutzPeter FischerRichard J PerrinNigel J CairnsErin E FranklinHerbert T CohenTowfique RajInma CobosBess FrostAlison GoateCharles L White IIIJohn F Crary
- Resource Type
- Journal article
- Publication Details
- Acta neuropathologica, Vol.143(1), pp.33-53
- DOI
- 10.1007/s00401-021-02379-z
- PMID
- 34719765
- PMCID
- PMC8786260
- NLM abbreviation
- Acta Neuropathol
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 AG054008, R01 NS095252, R01 AG060961, R01 NS086736, F32 AG056098, P30 AG066514, P50 AG005138, P30 AG066514, 75N95019C00049, K99 AG070109, R01 AG062348, P50 AG008702, U54 NS115266, R01 CA079830, P30 AG010124, P01 AG017586, U19 AG062418, P30 AG072979, P01 AG066597, R01 AG066152, R01 AG066152, P30 AG066468, U24 NS072026, P30 AG019610, P30 AG013854, P30 NS055077, P50 AG025688, P30 AG08017, R01 AG059848, P50 AG05134, AG10161, R01 AG021055, P50 AG016573, P01 AG000538, P30 AG062429, P50 AG005131, P30 AG028383, P50 AG005136, P30 AG066509, U01 AG006781, U19 066567, P30 AG066444, P01 AG003991, P01 AG026276, P01AG000538; DOI: 10.13039/100016608, name: Rainwater Charitable Foundation; DOI: 10.13039/100004328, name: Genentech; name: Alexander Saint-Amand Fellowship; DOI: 10.13039/100007306, name: The Arizona Department of Health Services; DOI: 10.13039/100000864, name: Michael J. Fox Foundation for Parkinson's Research; name: Winspear Family Center for Research on the Neuropathology of Alzheimer Disease; name: Rossy Foundation; DOI: 10.13039/501100003136, name: Edmond J. Safra Philanthropic Foundation; DOI: 10.13039/100007512, name: Nancy and Buster Alvord Endowment; DOI: 10.13039/501100000265, name: UK Medical Research Council, award: G0400074; name: Brains for Dementia research; name: Alzheimer’s Society and Alzheimer’s Research UK; DOI: 10.13039/501100003776, name: Newcastle upon Tyne Hospitals NHS Foundation Trust
- Language
- English
- Date published
- 11/01/2021
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984193262002771
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