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

Farrell, K.; Kim, S.; Han, N.; Iida, M. A.; Gonzalez, E.; Otero-Garcia, M.; Walker, J.; Richardson, T.; Renton, A. E.; Andrews, S. J.; Fulton-Howard, B.; Humphrey, J.; Vialle, R. A.; Bowles, K. R.; Whitney, K.; Dangoor, D. K.; Marcora, E.; Hefti, M. M.; Casella, A.; Bhangale, T.; Hunkapiller, J.; Ayalon, G.; Graham, R.; Cherry, J. D.; Cortes, E.; Borukov, V.; 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,

doi:10.1101/2021.06.30.450599

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bioRxiv · 10.1101/2021.06.30.450599

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

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Abstract

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy 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-{beta} (A{beta}) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from A{beta} 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 adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, 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 brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. 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 mediator of neurofibrillary degeneration.

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Farrell, K., Kim, S., Han, N., Iida, M. A., Gonzalez, E., Otero-Garcia, M., Walker, J., Richardson, T., Renton, A. E., Andrews, S. J., Fulton-Howard, B., Humphrey, J., Vialle, R. A., Bowles, K. R., Whitney, K., Dangoor, D. K., Marcora, E., Hefti, M. M., Casella, A., Bhangale, T., Hunkapiller, J., Ayalon, G., Graham, R., Cherry, J. D., Cortes, E., Borukov, V., 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,. 2021-07-01. Genome-wide association study and functional validation implicates JADE1 in tauopathy. https://doi.org/10.1101/2021.06.30.450599

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