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

Author(s): Farrell, K; Kim, S; Han, N; Iida, MA; Gonzalez, EM; Otero-Garcia, M; Walker, JM; Richardson, TE; Renton, AE; Andrews, SJ; Fulton-Howard, B; Humphrey, J; Vialle, RA; Bowles, KR; de Paiva Lopes, K; Whitney, K; Dangoor, DK; Walsh, H; Marcora, E; Hefti, MM; Casella, A; Sissoko, CT; Kapoor, M; Novikova, G; Udine, E; Wong, G; Tang, W; Bhangale, T; Hunkapiller, J; Ayalon, G; Graham, RR; Cherry, JD; Cortes, EP; Borukov, VY; McKee, AC; Stein, TD; Vonsattel, J; Teich, AF; Gearing, M; Glass, J; Troncoso, JC; Frosch, MP; Hyman, BT; Dickson, DW; Murray, ME; Attems, J; Flanagan, ME; Mao, Q; Mesulam, M; Weintraub, S; Woltjer, RL; Pham, T; Kofler, J; Schneider, JA; Yu, L; Purohit, DP; Haroutunian, V; Hof, PR; Gandy, S; Sano, M; Beach, TG; Poon, W; Kawas, CH; Corrada, MM; Rissman, RA; Metcalf, J; Shuldberg, S; Salehi, B; Nelson, PT; Trojanowski, JQ; Lee, EB; Wolk, DA; McMillan, CT; Keene, CD; Latimer, CS; Montine, TJ; Kovacs, GG; Lutz, MI; Fischer, P; Perrin, RJ; Cairns, NJ; Franklin, EE; Cohen, HT; Raj, T; Cobos, I; Frost, B; Goate, A; White Iii, CL; Crary, JF;
Year: 2022;  
Journal: Acta Neuropathologica;  
Volume: 143;  
Issue: 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 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.