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 independent...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Farrell, Kurt [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Anmerkung: |
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
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| Übergeordnetes Werk: |
Enthalten in: Acta neuropathologica - Berlin : Springer, 1961, 143(2021), 1 vom: 01. Nov., Seite 33-53 |
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| Übergeordnetes Werk: |
volume:143 ; year:2021 ; number:1 ; day:01 ; month:11 ; pages:33-53 |
| Links: |
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| DOI / URN: |
10.1007/s00401-021-02379-z |
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SPR04588854X |
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| 100 | 1 | |a Farrell, Kurt |e verfasserin |4 aut | |
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| 520 | |a 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. | ||
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10.1007/s00401-021-02379-z doi (DE-627)SPR04588854X (SPR)s00401-021-02379-z-e DE-627 ger DE-627 rakwb eng Farrell, Kurt verfasserin aut Genome-wide association study and functional validation implicates JADE1 in tauopathy 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 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. Kim, SoongHo aut Han, Natalia aut Iida, Megan A. aut Gonzalez, Elias M. aut Otero-Garcia, Marcos aut Walker, Jamie M. aut Richardson, Timothy E. aut Renton, Alan E. aut Andrews, Shea J. aut Fulton-Howard, Brian aut Humphrey, Jack aut Vialle, Ricardo A. aut Bowles, Kathryn R. aut de Paiva Lopes, Katia aut Whitney, Kristen aut Dangoor, Diana K. aut Walsh, Hadley aut Marcora, Edoardo aut Hefti, Marco M. aut Casella, Alicia aut Sissoko, Cheick T. aut Kapoor, Manav aut Novikova, Gloriia aut Udine, Evan aut Wong, Garrett aut Tang, Weijing aut Bhangale, Tushar aut Hunkapiller, Julie aut Ayalon, Gai aut Graham, Robert R. aut Cherry, Jonathan D. aut Cortes, Etty P. aut Borukov, Valeriy Y. aut McKee, Ann C. aut Stein, Thor D. aut Vonsattel, Jean-Paul aut Teich, Andy F. aut Gearing, Marla aut Glass, Jonathan aut Troncoso, Juan C. aut Frosch, Matthew P. aut Hyman, Bradley T. aut Dickson, Dennis W. aut Murray, Melissa E. aut Attems, Johannes aut Flanagan, Margaret E. aut Mao, Qinwen aut Mesulam, M.-Marsel aut Weintraub, Sandra aut Woltjer, Randy L. aut Pham, Thao aut Kofler, Julia aut Schneider, Julie A. aut Yu, Lei aut Purohit, Dushyant P. aut Haroutunian, Vahram aut Hof, Patrick R. aut Gandy, Sam aut Sano, Mary aut Beach, Thomas G. aut Poon, Wayne aut Kawas, Claudia H. aut Corrada, María M. aut Rissman, Robert A. aut Metcalf, Jeff aut Shuldberg, Sara aut Salehi, Bahar aut Nelson, Peter T. aut Trojanowski, John Q. aut Lee, Edward B. aut Wolk, David A. aut McMillan, Corey T. aut Keene, C. Dirk aut Latimer, Caitlin S. aut Montine, Thomas J. aut Kovacs, Gabor G. aut Lutz, Mirjam I. aut Fischer, Peter aut Perrin, Richard J. aut Cairns, Nigel J. aut Franklin, Erin E. aut Cohen, Herbert T. aut Raj, Towfique aut Cobos, Inma aut Frost, Bess aut Goate, Alison aut White III, Charles L. aut Crary, John F. (orcid)0000-0002-0556-293X aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 143(2021), 1 vom: 01. Nov., Seite 33-53 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:143 year:2021 number:1 day:01 month:11 pages:33-53 https://dx.doi.org/10.1007/s00401-021-02379-z lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 143 2021 1 01 11 33-53 |
| spelling |
10.1007/s00401-021-02379-z doi (DE-627)SPR04588854X (SPR)s00401-021-02379-z-e DE-627 ger DE-627 rakwb eng Farrell, Kurt verfasserin aut Genome-wide association study and functional validation implicates JADE1 in tauopathy 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 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. Kim, SoongHo aut Han, Natalia aut Iida, Megan A. aut Gonzalez, Elias M. aut Otero-Garcia, Marcos aut Walker, Jamie M. aut Richardson, Timothy E. aut Renton, Alan E. aut Andrews, Shea J. aut Fulton-Howard, Brian aut Humphrey, Jack aut Vialle, Ricardo A. aut Bowles, Kathryn R. aut de Paiva Lopes, Katia aut Whitney, Kristen aut Dangoor, Diana K. aut Walsh, Hadley aut Marcora, Edoardo aut Hefti, Marco M. aut Casella, Alicia aut Sissoko, Cheick T. aut Kapoor, Manav aut Novikova, Gloriia aut Udine, Evan aut Wong, Garrett aut Tang, Weijing aut Bhangale, Tushar aut Hunkapiller, Julie aut Ayalon, Gai aut Graham, Robert R. aut Cherry, Jonathan D. aut Cortes, Etty P. aut Borukov, Valeriy Y. aut McKee, Ann C. aut Stein, Thor D. aut Vonsattel, Jean-Paul aut Teich, Andy F. aut Gearing, Marla aut Glass, Jonathan aut Troncoso, Juan C. aut Frosch, Matthew P. aut Hyman, Bradley T. aut Dickson, Dennis W. aut Murray, Melissa E. aut Attems, Johannes aut Flanagan, Margaret E. aut Mao, Qinwen aut Mesulam, M.-Marsel aut Weintraub, Sandra aut Woltjer, Randy L. aut Pham, Thao aut Kofler, Julia aut Schneider, Julie A. aut Yu, Lei aut Purohit, Dushyant P. aut Haroutunian, Vahram aut Hof, Patrick R. aut Gandy, Sam aut Sano, Mary aut Beach, Thomas G. aut Poon, Wayne aut Kawas, Claudia H. aut Corrada, María M. aut Rissman, Robert A. aut Metcalf, Jeff aut Shuldberg, Sara aut Salehi, Bahar aut Nelson, Peter T. aut Trojanowski, John Q. aut Lee, Edward B. aut Wolk, David A. aut McMillan, Corey T. aut Keene, C. Dirk aut Latimer, Caitlin S. aut Montine, Thomas J. aut Kovacs, Gabor G. aut Lutz, Mirjam I. aut Fischer, Peter aut Perrin, Richard J. aut Cairns, Nigel J. aut Franklin, Erin E. aut Cohen, Herbert T. aut Raj, Towfique aut Cobos, Inma aut Frost, Bess aut Goate, Alison aut White III, Charles L. aut Crary, John F. (orcid)0000-0002-0556-293X aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 143(2021), 1 vom: 01. Nov., Seite 33-53 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:143 year:2021 number:1 day:01 month:11 pages:33-53 https://dx.doi.org/10.1007/s00401-021-02379-z lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 143 2021 1 01 11 33-53 |
| allfields_unstemmed |
10.1007/s00401-021-02379-z doi (DE-627)SPR04588854X (SPR)s00401-021-02379-z-e DE-627 ger DE-627 rakwb eng Farrell, Kurt verfasserin aut Genome-wide association study and functional validation implicates JADE1 in tauopathy 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 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. Kim, SoongHo aut Han, Natalia aut Iida, Megan A. aut Gonzalez, Elias M. aut Otero-Garcia, Marcos aut Walker, Jamie M. aut Richardson, Timothy E. aut Renton, Alan E. aut Andrews, Shea J. aut Fulton-Howard, Brian aut Humphrey, Jack aut Vialle, Ricardo A. aut Bowles, Kathryn R. aut de Paiva Lopes, Katia aut Whitney, Kristen aut Dangoor, Diana K. aut Walsh, Hadley aut Marcora, Edoardo aut Hefti, Marco M. aut Casella, Alicia aut Sissoko, Cheick T. aut Kapoor, Manav aut Novikova, Gloriia aut Udine, Evan aut Wong, Garrett aut Tang, Weijing aut Bhangale, Tushar aut Hunkapiller, Julie aut Ayalon, Gai aut Graham, Robert R. aut Cherry, Jonathan D. aut Cortes, Etty P. aut Borukov, Valeriy Y. aut McKee, Ann C. aut Stein, Thor D. aut Vonsattel, Jean-Paul aut Teich, Andy F. aut Gearing, Marla aut Glass, Jonathan aut Troncoso, Juan C. aut Frosch, Matthew P. aut Hyman, Bradley T. aut Dickson, Dennis W. aut Murray, Melissa E. aut Attems, Johannes aut Flanagan, Margaret E. aut Mao, Qinwen aut Mesulam, M.-Marsel aut Weintraub, Sandra aut Woltjer, Randy L. aut Pham, Thao aut Kofler, Julia aut Schneider, Julie A. aut Yu, Lei aut Purohit, Dushyant P. aut Haroutunian, Vahram aut Hof, Patrick R. aut Gandy, Sam aut Sano, Mary aut Beach, Thomas G. aut Poon, Wayne aut Kawas, Claudia H. aut Corrada, María M. aut Rissman, Robert A. aut Metcalf, Jeff aut Shuldberg, Sara aut Salehi, Bahar aut Nelson, Peter T. aut Trojanowski, John Q. aut Lee, Edward B. aut Wolk, David A. aut McMillan, Corey T. aut Keene, C. Dirk aut Latimer, Caitlin S. aut Montine, Thomas J. aut Kovacs, Gabor G. aut Lutz, Mirjam I. aut Fischer, Peter aut Perrin, Richard J. aut Cairns, Nigel J. aut Franklin, Erin E. aut Cohen, Herbert T. aut Raj, Towfique aut Cobos, Inma aut Frost, Bess aut Goate, Alison aut White III, Charles L. aut Crary, John F. (orcid)0000-0002-0556-293X aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 143(2021), 1 vom: 01. Nov., Seite 33-53 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:143 year:2021 number:1 day:01 month:11 pages:33-53 https://dx.doi.org/10.1007/s00401-021-02379-z lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 143 2021 1 01 11 33-53 |
| allfieldsGer |
10.1007/s00401-021-02379-z doi (DE-627)SPR04588854X (SPR)s00401-021-02379-z-e DE-627 ger DE-627 rakwb eng Farrell, Kurt verfasserin aut Genome-wide association study and functional validation implicates JADE1 in tauopathy 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 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. Kim, SoongHo aut Han, Natalia aut Iida, Megan A. aut Gonzalez, Elias M. aut Otero-Garcia, Marcos aut Walker, Jamie M. aut Richardson, Timothy E. aut Renton, Alan E. aut Andrews, Shea J. aut Fulton-Howard, Brian aut Humphrey, Jack aut Vialle, Ricardo A. aut Bowles, Kathryn R. aut de Paiva Lopes, Katia aut Whitney, Kristen aut Dangoor, Diana K. aut Walsh, Hadley aut Marcora, Edoardo aut Hefti, Marco M. aut Casella, Alicia aut Sissoko, Cheick T. aut Kapoor, Manav aut Novikova, Gloriia aut Udine, Evan aut Wong, Garrett aut Tang, Weijing aut Bhangale, Tushar aut Hunkapiller, Julie aut Ayalon, Gai aut Graham, Robert R. aut Cherry, Jonathan D. aut Cortes, Etty P. aut Borukov, Valeriy Y. aut McKee, Ann C. aut Stein, Thor D. aut Vonsattel, Jean-Paul aut Teich, Andy F. aut Gearing, Marla aut Glass, Jonathan aut Troncoso, Juan C. aut Frosch, Matthew P. aut Hyman, Bradley T. aut Dickson, Dennis W. aut Murray, Melissa E. aut Attems, Johannes aut Flanagan, Margaret E. aut Mao, Qinwen aut Mesulam, M.-Marsel aut Weintraub, Sandra aut Woltjer, Randy L. aut Pham, Thao aut Kofler, Julia aut Schneider, Julie A. aut Yu, Lei aut Purohit, Dushyant P. aut Haroutunian, Vahram aut Hof, Patrick R. aut Gandy, Sam aut Sano, Mary aut Beach, Thomas G. aut Poon, Wayne aut Kawas, Claudia H. aut Corrada, María M. aut Rissman, Robert A. aut Metcalf, Jeff aut Shuldberg, Sara aut Salehi, Bahar aut Nelson, Peter T. aut Trojanowski, John Q. aut Lee, Edward B. aut Wolk, David A. aut McMillan, Corey T. aut Keene, C. Dirk aut Latimer, Caitlin S. aut Montine, Thomas J. aut Kovacs, Gabor G. aut Lutz, Mirjam I. aut Fischer, Peter aut Perrin, Richard J. aut Cairns, Nigel J. aut Franklin, Erin E. aut Cohen, Herbert T. aut Raj, Towfique aut Cobos, Inma aut Frost, Bess aut Goate, Alison aut White III, Charles L. aut Crary, John F. (orcid)0000-0002-0556-293X aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 143(2021), 1 vom: 01. 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10.1007/s00401-021-02379-z doi (DE-627)SPR04588854X (SPR)s00401-021-02379-z-e DE-627 ger DE-627 rakwb eng Farrell, Kurt verfasserin aut Genome-wide association study and functional validation implicates JADE1 in tauopathy 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 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. Kim, SoongHo aut Han, Natalia aut Iida, Megan A. aut Gonzalez, Elias M. aut Otero-Garcia, Marcos aut Walker, Jamie M. aut Richardson, Timothy E. aut Renton, Alan E. aut Andrews, Shea J. aut Fulton-Howard, Brian aut Humphrey, Jack aut Vialle, Ricardo A. aut Bowles, Kathryn R. aut de Paiva Lopes, Katia aut Whitney, Kristen aut Dangoor, Diana K. aut Walsh, Hadley aut Marcora, Edoardo aut Hefti, Marco M. aut Casella, Alicia aut Sissoko, Cheick T. aut Kapoor, Manav aut Novikova, Gloriia aut Udine, Evan aut Wong, Garrett aut Tang, Weijing aut Bhangale, Tushar aut Hunkapiller, Julie aut Ayalon, Gai aut Graham, Robert R. aut Cherry, Jonathan D. aut Cortes, Etty P. aut Borukov, Valeriy Y. aut McKee, Ann C. aut Stein, Thor D. aut Vonsattel, Jean-Paul aut Teich, Andy F. aut Gearing, Marla aut Glass, Jonathan aut Troncoso, Juan C. aut Frosch, Matthew P. aut Hyman, Bradley T. aut Dickson, Dennis W. aut Murray, Melissa E. aut Attems, Johannes aut Flanagan, Margaret E. aut Mao, Qinwen aut Mesulam, M.-Marsel aut Weintraub, Sandra aut Woltjer, Randy L. aut Pham, Thao aut Kofler, Julia aut Schneider, Julie A. aut Yu, Lei aut Purohit, Dushyant P. aut Haroutunian, Vahram aut Hof, Patrick R. aut Gandy, Sam aut Sano, Mary aut Beach, Thomas G. aut Poon, Wayne aut Kawas, Claudia H. aut Corrada, María M. aut Rissman, Robert A. aut Metcalf, Jeff aut Shuldberg, Sara aut Salehi, Bahar aut Nelson, Peter T. aut Trojanowski, John Q. aut Lee, Edward B. aut Wolk, David A. aut McMillan, Corey T. aut Keene, C. Dirk aut Latimer, Caitlin S. aut Montine, Thomas J. aut Kovacs, Gabor G. aut Lutz, Mirjam I. aut Fischer, Peter aut Perrin, Richard J. aut Cairns, Nigel J. aut Franklin, Erin E. aut Cohen, Herbert T. aut Raj, Towfique aut Cobos, Inma aut Frost, Bess aut Goate, Alison aut White III, Charles L. aut Crary, John F. (orcid)0000-0002-0556-293X aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 143(2021), 1 vom: 01. Nov., Seite 33-53 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:143 year:2021 number:1 day:01 month:11 pages:33-53 https://dx.doi.org/10.1007/s00401-021-02379-z lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 143 2021 1 01 11 33-53 |
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Farrell, Kurt @@aut@@ Kim, SoongHo @@aut@@ Han, Natalia @@aut@@ Iida, Megan A. @@aut@@ Gonzalez, Elias M. @@aut@@ Otero-Garcia, Marcos @@aut@@ Walker, Jamie M. @@aut@@ Richardson, Timothy E. @@aut@@ Renton, Alan E. @@aut@@ Andrews, Shea J. @@aut@@ Fulton-Howard, Brian @@aut@@ Humphrey, Jack @@aut@@ Vialle, Ricardo A. @@aut@@ Bowles, Kathryn R. @@aut@@ de Paiva Lopes, Katia @@aut@@ Whitney, Kristen @@aut@@ Dangoor, Diana K. @@aut@@ Walsh, Hadley @@aut@@ Marcora, Edoardo @@aut@@ Hefti, Marco M. @@aut@@ Casella, Alicia @@aut@@ Sissoko, Cheick T. @@aut@@ Kapoor, Manav @@aut@@ Novikova, Gloriia @@aut@@ Udine, Evan @@aut@@ Wong, Garrett @@aut@@ Tang, Weijing @@aut@@ Bhangale, Tushar @@aut@@ Hunkapiller, Julie @@aut@@ Ayalon, Gai @@aut@@ Graham, Robert R. @@aut@@ Cherry, Jonathan D. @@aut@@ Cortes, Etty P. @@aut@@ Borukov, Valeriy Y. @@aut@@ McKee, Ann C. @@aut@@ Stein, Thor D. @@aut@@ Vonsattel, Jean-Paul @@aut@@ Teich, Andy F. @@aut@@ Gearing, Marla @@aut@@ Glass, Jonathan @@aut@@ Troncoso, Juan C. @@aut@@ Frosch, Matthew P. @@aut@@ Hyman, Bradley T. @@aut@@ Dickson, Dennis W. @@aut@@ Murray, Melissa E. @@aut@@ Attems, Johannes @@aut@@ Flanagan, Margaret E. @@aut@@ Mao, Qinwen @@aut@@ Mesulam, M.-Marsel @@aut@@ Weintraub, Sandra @@aut@@ Woltjer, Randy L. @@aut@@ Pham, Thao @@aut@@ Kofler, Julia @@aut@@ Schneider, Julie A. @@aut@@ Yu, Lei @@aut@@ Purohit, Dushyant P. @@aut@@ Haroutunian, Vahram @@aut@@ Hof, Patrick R. @@aut@@ Gandy, Sam @@aut@@ Sano, Mary @@aut@@ Beach, Thomas G. @@aut@@ Poon, Wayne @@aut@@ Kawas, Claudia H. @@aut@@ Corrada, María M. @@aut@@ Rissman, Robert A. @@aut@@ Metcalf, Jeff @@aut@@ Shuldberg, Sara @@aut@@ Salehi, Bahar @@aut@@ Nelson, Peter T. @@aut@@ Trojanowski, John Q. @@aut@@ Lee, Edward B. @@aut@@ Wolk, David A. @@aut@@ McMillan, Corey T. @@aut@@ Keene, C. Dirk @@aut@@ Latimer, Caitlin S. @@aut@@ Montine, Thomas J. @@aut@@ Kovacs, Gabor G. @@aut@@ Lutz, Mirjam I. @@aut@@ Fischer, Peter @@aut@@ Perrin, Richard J. @@aut@@ Cairns, Nigel J. @@aut@@ Franklin, Erin E. @@aut@@ Cohen, Herbert T. @@aut@@ Raj, Towfique @@aut@@ Cobos, Inma @@aut@@ Frost, Bess @@aut@@ Goate, Alison @@aut@@ White III, Charles L. @@aut@@ Crary, John F. @@aut@@ |
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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. Casella, Alicia Sissoko, Cheick T. Kapoor, Manav Novikova, Gloriia Udine, Evan Wong, Garrett Tang, Weijing Bhangale, Tushar Hunkapiller, Julie Ayalon, Gai Graham, Robert R. Cherry, Jonathan D. Cortes, Etty P. Borukov, Valeriy Y. McKee, Ann C. Stein, Thor D. Vonsattel, Jean-Paul Teich, Andy F. Gearing, Marla Glass, Jonathan Troncoso, Juan C. Frosch, Matthew P. Hyman, Bradley T. Dickson, Dennis W. Murray, Melissa E. Attems, Johannes Flanagan, Margaret E. Mao, Qinwen Mesulam, M.-Marsel Weintraub, Sandra Woltjer, Randy L. Pham, Thao Kofler, Julia Schneider, Julie A. Yu, Lei Purohit, Dushyant P. Haroutunian, Vahram Hof, Patrick R. Gandy, Sam Sano, Mary Beach, Thomas G. Poon, Wayne Kawas, Claudia H. Corrada, María M. Rissman, Robert A. Metcalf, Jeff Shuldberg, Sara Salehi, Bahar Nelson, Peter T. Trojanowski, John Q. Lee, Edward B. Wolk, David A. McMillan, Corey T. Keene, C. Dirk Latimer, Caitlin S. Montine, Thomas J. Kovacs, Gabor G. Lutz, Mirjam I. Fischer, Peter Perrin, Richard J. Cairns, Nigel J. Franklin, Erin E. Cohen, Herbert T. Raj, Towfique Cobos, Inma Frost, Bess Goate, Alison White III, Charles L. Crary, John F. |
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genome-wide association study and functional validation implicates jade1 in tauopathy |
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Genome-wide association study and functional validation implicates JADE1 in tauopathy |
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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. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
| abstractGer |
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. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
| abstract_unstemmed |
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. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
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| score |
7.401458 |