Farrell, K., Kim, S., Han, N., Iida, M.A., Gonzalez, E.M., Otero-Garcia, M., Walker, J.M., Richardson, T.E., Renton, A.E., Andrews, S.J., Fulton-Howard, B., Humphrey, J., Vialle, R.A., Bowles, K.R., de Paiva Lopes, K., Whitney, K., Dangoor, D.K., Walsh, H., Marcora, E., Hefti, M.M., Casella, A., Sissoko, C.T., Kapoor, M., Novikova, G., Udine, E., Wong, G., Tang, W., Bhangale, T., Hunkapiller, J., Ayalon, G., Graham, R.R., Cherry, J.D., Cortes, E.P., Borukov, V.Y., McKee, A.C., Stein, T.D., Vonsattel, J.P., Teich, A.F., Gearing, M., Glass, J., Troncoso, J.C., Frosch, M.P., Hyman, B.T., Dickson, D.W., Murray, M.E., Attems, J., Flanagan, M.E., Mao, Q., Mesulam, M.M., Weintraub, S., Woltjer, R.L., Pham, T., Kofler, J., Schneider, J.A., Yu, L., Purohit, D.P., Haroutunian, V., Hof, P.R., Gandy, S., Sano, M., Beach, T.G., Poon, W., Kawas, C.H., Corrada, M.M., Rissman, R.A., Metcalf, J., Shuldberg, S., Salehi, B., Nelson, P.T., Trojanowski, J.Q., Lee, E.B., Wolk, D.A., McMillan, C.T., Keene, C.D., Latimer, C.S., Montine, T.J., Kovacs, G.G., Lutz, M.I., Fischer, P., Perrin, R.J., Cairns, N.J., Franklin, E.E., Cohen, H.T., Raj, T., Cobos, I., Frost, B., Goate, A., White Iii, C.L., Crary, J.F. (2022). Genome-wide association study and functional validation implicates JADE1 in tauopathy.  Acta Neuropathol. 143(1): 33--53.

FBrf0252319

Research paper

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.

PMC8786260 (PMC) (EuropePMC)