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http://purl.uniprot.org/citations/34719765http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/34719765http://www.w3.org/2000/01/rdf-schema#comment"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."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.org/dc/terms/identifier"doi:10.1007/s00401-021-02379-z"xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Kim S."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Fischer P."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Sano M."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Metcalf J."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Tang W."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Yu L."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Walker J.M."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Cairns N.J."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Dickson D.W."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Glass J."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Graham R.R."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Pham T."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Kapoor M."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Frosch M.P."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Goate A."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Hyman B.T."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Han N."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Farrell K."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Gonzalez E.M."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Bowles K.R."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Gearing M."xsd:string
http://purl.uniprot.org/citations/34719765http://purl.uniprot.org/core/author"Woltjer R.L."xsd:string
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