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

Kurt Farrell; Soong Ho Kim; Natalia Han; Megan A. Iida; Elias M. Gonzalez; Marcos Otero-Garcia; Jamie M. Walker; Timothy E. Richardson; Alan E. Renton; Shea J. Andrews; Brian Fulton-Howard; Jack Humphrey; Ricardo A. Vialle; Kathryn R. Bowles; Katia de Paiva Lopes; Kristen Whitney; Diana K. Dangoor; Hadley Walsh; Edoardo Marcora; Marco M. Hefti; Alicia Casella; Cheick T. Sissoko; Manav Kapoor; Gloriia Novikova; Evan Udine; Garrett Wong; Weijing Tang; Tushar Bhangale; Julie Hunkapiller; Gai Ayalon; Robert R. Graham; Jonathan D. Cherry; Etty P. Cortes; Valeriy Y. Borukov; Ann C. McKee; Thor D. Stein; Jean Paul Vonsattel; Andy F. Teich; Marla Gearing; Jonathan Glass; Juan C. Troncoso; Matthew P. Frosch; Bradley T. Hyman; Dennis W. Dickson; Melissa E. Murray; Johannes Attems; Margaret E. Flanagan; Qinwen Mao; M. Marsel Mesulam; Sandra Weintraub; Randy L. Woltjer; Thao Pham; Julia Kofler; Julie A. Schneider; Lei Yu; Dushyant P. Purohit; Vahram Haroutunian; Patrick R. Hof; Sam Gandy; Mary Sano; Thomas G. Beach; Wayne Poon; Claudia H. Kawas; María M. Corrada; Robert A. Rissman; Jeff Metcalf; Sara Shuldberg; Bahar Salehi; Peter T. Nelson; John Q. Trojanowski; Edward B. Lee; David A. Wolk; Corey T. McMillan; C. Dirk Keene; Caitlin S. Latimer; Thomas J. Montine; Gabor G. Kovacs; Mirjam I. Lutz; Peter Fischer; Richard J. Perrin; Nigel J. Cairns; Erin E. Franklin; Herbert T. Cohen; Towfique Raj; Inma Cobos; Bess Frost; Alison Goate; Charles L. White; John F. Crary

doi:10.1007/s00401-021-02379-z

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

Kurt Farrell, Soong Ho Kim, Natalia Han, Megan A. Iida, Elias M. Gonzalez, Marcos Otero-Garcia, Jamie M. Walker, Timothy E. Richardson, Alan E. Renton, Shea J. Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A. Vialle, Kathryn R. Bowles, Katia de Paiva Lopes, Kristen Whitney, Diana K. Dangoor, Hadley Walsh, Edoardo Marcora, Marco M. HeftiAlicia Casella, Cheick T. Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Robert R. Graham, Jonathan D. Cherry, Etty P. Cortes, Valeriy Y. Borukov, Ann C. McKee, Thor D. Stein, Jean Paul Vonsattel, Andy F. Teich, Marla Gearing, Jonathan Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Dennis W. Dickson, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M. Marsel Mesulam, Sandra Weintraub, Randy L. Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne Poon, Claudia H. Kawas, María M. Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, C. Dirk Keene, Caitlin S. Latimer, Thomas J. Montine, Gabor G. Kovacs, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel J. Cairns, Erin E. Franklin, Herbert T. Cohen, Towfique Raj, Inma Cobos, Bess Frost, Alison Goate, Charles L. White, John F. Crary

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	33-53
Number of pages	21
Journal	Acta Neuropathologica
Volume	143
Issue number	1
DOIs	https://doi.org/10.1007/s00401-021-02379-z
State	Published - Jan 2022

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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Farrell, K., Kim, S. H., 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., ... Crary, J. F. (2022). Genome-wide association study and functional validation implicates JADE1 in tauopathy. Acta Neuropathologica, 143(1), 33-53. https://doi.org/10.1007/s00401-021-02379-z

Farrell, K, Kim, SH, 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, JP, Teich, AF, Gearing, M, Glass, J, Troncoso, JC, Frosch, MP, Hyman, BT, Dickson, DW, Murray, ME, Attems, J, Flanagan, ME, Mao, Q, Mesulam, MM, 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, CL & Crary, JF 2022, 'Genome-wide association study and functional validation implicates JADE1 in tauopathy', Acta Neuropathologica, vol. 143, no. 1, pp. 33-53. https://doi.org/10.1007/s00401-021-02379-z

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title = "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.",

author = "Kurt Farrell and Kim, {Soong Ho} and Natalia Han and Iida, {Megan A.} and Gonzalez, {Elias M.} and Marcos Otero-Garcia and Walker, {Jamie M.} and Richardson, {Timothy E.} and Renton, {Alan E.} and Andrews, {Shea J.} and Brian Fulton-Howard and Jack Humphrey and Vialle, {Ricardo A.} and Bowles, {Kathryn R.} and {de Paiva Lopes}, Katia and Kristen Whitney and Dangoor, {Diana K.} and Hadley Walsh and Edoardo Marcora and Hefti, {Marco M.} and Alicia Casella and Sissoko, {Cheick T.} and Manav Kapoor and Gloriia Novikova and Evan Udine and Garrett Wong and Weijing Tang and Tushar Bhangale and Julie Hunkapiller and Gai Ayalon and Graham, {Robert R.} and Cherry, {Jonathan D.} and Cortes, {Etty P.} and Borukov, {Valeriy Y.} and McKee, {Ann C.} and Stein, {Thor D.} and Vonsattel, {Jean Paul} and Teich, {Andy F.} and Marla Gearing and Jonathan Glass and Troncoso, {Juan C.} and Frosch, {Matthew P.} and Hyman, {Bradley T.} and Dickson, {Dennis W.} and Murray, {Melissa E.} and Johannes Attems and Flanagan, {Margaret E.} and Qinwen Mao and Mesulam, {M. Marsel} and Sandra Weintraub and Woltjer, {Randy L.} and Thao Pham and Julia Kofler and Schneider, {Julie A.} and Lei Yu and Purohit, {Dushyant P.} and Vahram Haroutunian and Hof, {Patrick R.} and Sam Gandy and Mary Sano and Beach, {Thomas G.} and Wayne Poon and Kawas, {Claudia H.} and Corrada, {Mar{\'i}a M.} and Rissman, {Robert A.} and Jeff Metcalf and Sara Shuldberg and Bahar Salehi and Nelson, {Peter T.} and Trojanowski, {John Q.} and Lee, {Edward B.} and Wolk, {David A.} and McMillan, {Corey T.} and Keene, {C. Dirk} and Latimer, {Caitlin S.} and Montine, {Thomas J.} and Kovacs, {Gabor G.} and Lutz, {Mirjam I.} and Peter Fischer and Perrin, {Richard J.} and Cairns, {Nigel J.} and Franklin, {Erin E.} and Cohen, {Herbert T.} and Towfique Raj and Inma Cobos and Bess Frost and Alison Goate and White, {Charles L.} and Crary, {John F.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2022",

month = jan,

doi = "10.1007/s00401-021-02379-z",

language = "English (US)",

volume = "143",

pages = "33--53",

journal = "Acta Neuropathologica",

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number = "1",

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TY - JOUR

T1 - Genome-wide association study and functional validation implicates JADE1 in tauopathy

AU - Farrell, Kurt

AU - Kim, Soong Ho

AU - Han, Natalia

AU - Iida, Megan A.

AU - Gonzalez, Elias M.

AU - Otero-Garcia, Marcos

AU - Walker, Jamie M.

AU - Richardson, Timothy E.

AU - Renton, Alan E.

AU - Andrews, Shea J.

AU - Fulton-Howard, Brian

AU - Humphrey, Jack

AU - Vialle, Ricardo A.

AU - Bowles, Kathryn R.

AU - de Paiva Lopes, Katia

AU - Whitney, Kristen

AU - Dangoor, Diana K.

AU - Walsh, Hadley

AU - Marcora, Edoardo

AU - Hefti, Marco M.

AU - Casella, Alicia

AU - Sissoko, Cheick T.

AU - Kapoor, Manav

AU - Novikova, Gloriia

AU - Udine, Evan

AU - Wong, Garrett

AU - Tang, Weijing

AU - Bhangale, Tushar

AU - Hunkapiller, Julie

AU - Ayalon, Gai

AU - Graham, Robert R.

AU - Cherry, Jonathan D.

AU - Cortes, Etty P.

AU - Borukov, Valeriy Y.

AU - McKee, Ann C.

AU - Stein, Thor D.

AU - Vonsattel, Jean Paul

AU - Teich, Andy F.

AU - Gearing, Marla

AU - Glass, Jonathan

AU - Troncoso, Juan C.

AU - Frosch, Matthew P.

AU - Hyman, Bradley T.

AU - Dickson, Dennis W.

AU - Murray, Melissa E.

AU - Attems, Johannes

AU - Flanagan, Margaret E.

AU - Mao, Qinwen

AU - Mesulam, M. Marsel

AU - Weintraub, Sandra

AU - Woltjer, Randy L.

AU - Pham, Thao

AU - Kofler, Julia

AU - Schneider, Julie A.

AU - Yu, Lei

AU - Purohit, Dushyant P.

AU - Haroutunian, Vahram

AU - Hof, Patrick R.

AU - Gandy, Sam

AU - Sano, Mary

AU - Beach, Thomas G.

AU - Poon, Wayne

AU - Kawas, Claudia H.

AU - Corrada, María M.

AU - Rissman, Robert A.

AU - Metcalf, Jeff

AU - Shuldberg, Sara

AU - Salehi, Bahar

AU - Nelson, Peter T.

AU - Trojanowski, John Q.

AU - Lee, Edward B.

AU - Wolk, David A.

AU - McMillan, Corey T.

AU - Keene, C. Dirk

AU - Latimer, Caitlin S.

AU - Montine, Thomas J.

AU - Kovacs, Gabor G.

AU - Lutz, Mirjam I.

AU - Fischer, Peter

AU - Perrin, Richard J.

AU - Cairns, Nigel J.

AU - Franklin, Erin E.

AU - Cohen, Herbert T.

AU - Raj, Towfique

AU - Cobos, Inma

AU - Frost, Bess

AU - Goate, Alison

AU - White, Charles L.

AU - Crary, John F.

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

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U2 - 10.1007/s00401-021-02379-z

DO - 10.1007/s00401-021-02379-z

M3 - Article

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AN - SCOPUS:85118310740

SN - 0001-6322

VL - 143

SP - 33

EP - 53

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 1

ER -

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

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