| Literature DB >> 34719765 |
Kurt Farrell1,2,3, SoongHo Kim1,2,3, Natalia Han1,2,3, Megan A Iida1,2,3, Elias M Gonzalez4, Marcos Otero-Garcia5, Jamie M Walker6, Timothy E Richardson6, Alan E Renton2,7, Shea J Andrews2,7, Brian Fulton-Howard2,7, Jack Humphrey2,7, Ricardo A Vialle2,7, Kathryn R Bowles7, Katia de Paiva Lopes2,7, Kristen Whitney1,2,3, Diana K Dangoor1,2,3, Hadley Walsh1,2,3, Edoardo Marcora2,7, Marco M Hefti8, Alicia Casella1,2,3, Cheick T Sissoko1,2,3, Manav Kapoor2,7, Gloriia Novikova2,7, Evan Udine2,7, Garrett Wong2,7, Weijing Tang9, Tushar Bhangale10, Julie Hunkapiller10, Gai Ayalon11, Robert R Graham12, Jonathan D Cherry13, Etty P Cortes1,2, Valeriy Y Borukov1,2, Ann C McKee13, Thor D Stein13, Jean-Paul Vonsattel14, Andy F Teich14, Marla Gearing15, Jonathan Glass15, Juan C Troncoso16, Matthew P Frosch17, Bradley T Hyman17, Dennis W Dickson18, Melissa E Murray18, Johannes Attems19, Margaret E Flanagan20, Qinwen Mao20, M-Marsel Mesulam20, Sandra Weintraub20, Randy L Woltjer21, Thao Pham21, Julia Kofler22, Julie A Schneider23, Lei Yu23, Dushyant P Purohit1,24, Vahram Haroutunian2,24, Patrick R Hof2, Sam Gandy24,25, Mary Sano24, Thomas G Beach26, Wayne Poon27, Claudia H Kawas28, María M Corrada27, Robert A Rissman29, Jeff Metcalf29, Sara Shuldberg29, Bahar Salehi29, Peter T Nelson30, John Q Trojanowski31, Edward B Lee31, David A Wolk32, Corey T McMillan32, C Dirk Keene33, Caitlin S Latimer33, Thomas J Montine33,9, Gabor G Kovacs34,35,36, Mirjam I Lutz36, Peter Fischer37, Richard J Perrin38, Nigel J Cairns39, Erin E Franklin38, Herbert T Cohen40, Towfique Raj2,7, Inma Cobos9, Bess Frost4, Alison Goate2,7, Charles L White Iii41, John F Crary42,43,44.
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.Entities:
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Year: 2021 PMID： 34719765 PMCID： PMC8786260 DOI： 10.1007/s00401-021-02379-z
Source DB: PubMed Journal: Acta Neuropathol ISSN： 0001-6322 Impact factor: 15.887