Genome-wide association study and functional validation implicates JADE1 in tauopathy.
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 CraryPublished in: Acta neuropathologica (2021)
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.
Keyphrases
- genome wide
- single cell
- genome wide association study
- rna seq
- cerebrospinal fluid
- genome wide association
- cognitive impairment
- oxidative stress
- multiple sclerosis
- mild cognitive impairment
- copy number
- dna methylation
- white matter
- binding protein
- mass spectrometry
- high resolution
- endoplasmic reticulum stress
- ms ms
- high glucose
- resting state
- amino acid
- dna binding
- drug delivery
- high throughput sequencing