Dataset Information

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

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.

SUBMITTER: Farrell K

PROVIDER: S-EPMC8786260 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Farrell Kurt K Kim SoongHo S Han Natalia N Iida Megan A MA Gonzalez Elias M EM Otero-Garcia Marcos M Walker Jamie M JM Richardson Timothy E TE Renton Alan E AE Andrews Shea J SJ Fulton-Howard Brian B Humphrey Jack J Vialle Ricardo A RA Bowles Kathryn R KR de Paiva Lopes Katia K Whitney Kristen K Dangoor Diana K DK Walsh Hadley H Marcora Edoardo E Hefti Marco M MM Casella Alicia A Sissoko Cheick T CT Kapoor Manav M Novikova Gloriia G Udine Evan E Wong Garrett G Tang Weijing W Bhangale Tushar T Hunkapiller Julie J Ayalon Gai G Graham Robert R RR Cherry Jonathan D JD Cortes Etty P EP Borukov Valeriy Y VY McKee Ann C AC Stein Thor D TD Vonsattel Jean-Paul JP Teich Andy F AF Gearing Marla M Glass Jonathan J Troncoso Juan C JC Frosch Matthew P MP Hyman Bradley T BT Dickson Dennis W DW Murray Melissa E ME Attems Johannes J Flanagan Margaret E ME Mao Qinwen Q Mesulam M-Marsel MM Weintraub Sandra S Woltjer Randy L RL Pham Thao T Kofler Julia J Schneider Julie A JA Yu Lei L Purohit Dushyant P DP Haroutunian Vahram V Hof Patrick R PR Gandy Sam S Sano Mary M Beach Thomas G TG Poon Wayne W Kawas Claudia H CH Corrada María M MM Rissman Robert A RA Metcalf Jeff J Shuldberg Sara S Salehi Bahar B Nelson Peter T PT Trojanowski John Q JQ Lee Edward B EB Wolk David A DA McMillan Corey T CT Keene C Dirk CD Latimer Caitlin S CS Montine Thomas J TJ Kovacs Gabor G GG Lutz Mirjam I MI Fischer Peter P Perrin Richard J RJ Cairns Nigel J NJ Franklin Erin E EE Cohen Herbert T HT Raj Towfique T Cobos Inma I Frost Bess B Goate Alison A White Iii Charles L CL Crary John F JF

Acta neuropathologica 20211101 1

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 ge ...[more]

PMID: 34719765

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Dataset Information

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Publications

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

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