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- Title
Genome-wide association study and functional validation implicates JADE1 in tauopathy.
- Authors
Farrell, Kurt; Kim, SoongHo; Han, Natalia; Iida, Megan A.; Gonzalez, Elias M.; Otero-Garcia, Marcos; Walker, Jamie M.; Richardson, Timothy E.; Renton, Alan E.; Andrews, Shea J.; Fulton-Howard, Brian; Humphrey, Jack; Vialle, Ricardo A.; Bowles, Kathryn R.; de Paiva Lopes, Katia; Whitney, Kristen; Dangoor, Diana K.; Walsh, Hadley; Marcora, Edoardo; Hefti, Marco M.
- 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.
- Subjects
GENOME-wide association studies; CHROMOSOME polymorphism; PROGRESSIVE supranuclear palsy; SINGLE nucleotide polymorphisms; MICROTUBULES; TEMPORAL lobe; NEUROFIBRILLARY tangles; TAUOPATHIES
- Publication
Acta Neuropathologica, 2022, Vol 143, Issue 1, p33
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-021-02379-z