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

被引：20

作者：

Farrell, Kurt ^{[1
,2
,3
]}

Kim, SoongHo ^{[1
,2
,3
]}

Han, Natalia ^{[1
,2
,3
]}

Iida, Megan A. ^{[1
,2
,3
]}

Gonzalez, Elias M. ^{[4
]}

Otero-Garcia, Marcos ^{[5
]}

Walker, Jamie M. ^{[6
,7
]}

Richardson, Timothy E. ^{[6
,7
]}

Renton, Alan E. ^{[2
,8
]}

Andrews, Shea J. ^{[2
,8
]}

Fulton-Howard, Brian ^{[2
,8
]}

Humphrey, Jack ^{[2
,8
]}

Vialle, Ricardo A. ^{[2
,8
]}

Bowles, Kathryn R. ^{[8
]}

Lopes, Katia de Paiva ^{[2
,8
]}

Whitney, Kristen ^{[1
,2
,3
]}

Dangoor, Diana K. ^{[1
,2
,3
]}

Walsh, Hadley ^{[1
,2
,3
]}

Marcora, Edoardo ^{[2
,8
]}

Hefti, Marco M. ^{[9
]}

Casella, Alicia ^{[1
,2
,3
]}

Sissoko, Cheick T. ^{[1
,2
,3
]}

Kapoor, Manav ^{[2
,8
]}

Novikova, Gloriia ^{[2
,8
]}

Udine, Evan ^{[2
,8
]}

Wong, Garrett ^{[2
,8
]}

Tang, Weijing ^{[38
]}

Bhangale, Tushar ^{[10
]}

Hunkapiller, Julie ^{[10
]}

Ayalon, Gai ^{[11
]}

Graham, Robert R. ^{[12
]}

Cherry, Jonathan D. ^{[13
]}

Cortes, Etty P. ^{[1
,2
]}

Borukov, Valeriy Y. ^{[1
,2
]}

McKee, Ann C. ^{[13
]}

Stein, Thor D. ^{[13
]}

Vonsattel, Jean-Paul ^{[14
,15
,16
]}

Teich, Andy F. ^{[14
,15
,16
]}

Gearing, Marla ^{[17
]}

Glass, Jonathan ^{[17
]}

Troncoso, Juan C. ^{[18
]}

Frosch, Matthew P. ^{[19
,20
]}

Hyman, Bradley T. ^{[19
,20
]}

Dickson, Dennis W. ^{[21
]}

Murray, Melissa E. ^{[21
]}

Attems, Johannes ^{[22
]}

Flanagan, Margaret E. ^{[23
]}

Mao, Qinwen ^{[23
]}

Mesulam, M-Marsel ^{[23
]}

Weintraub, Sandra ^{[23
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Pathol, Neuropathol Brain Bank & Res CoRE, 1 Gustave L Levy Pl Box 1194, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Nash Dept Neurosci, Ronald M Loeb Ctr Alzheimers Dis, Friedman Brain Inst, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Artificial Intelligence & Human Hlth, New York, NY 10029 USA

[4] Univ Texas Hlth San Antonio, Dept Cell Syst & Anat, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[5] Univ Calif Los Angeles, Div Neuropathol, Dept Pathol & Lab Med, Los Angeles, CA USA

[6] UT Hlth San Antonio, Dept Pathol, San Antonio, TX USA

[7] UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA

[8] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[9] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA

[10] Genentech Inc, Dept Human Genet, San Francisco, CA 94080 USA

[11] Neumora Therapeut, San Francisco, CA USA

[12] Maze Therapeut, San Francisco, CA USA

[13] Boston Univ, Sch Med, Dept Pathol Neuropathol, VA Med Ctr, Boston, MA 02118 USA

[14] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA

[15] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA

[16] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[17] Emory Univ, Sch Med, Dept Pathol & Lab Med Neuropathol & Neurol, Atlanta, GA USA

[18] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA

[19] Harvard Med Sch, Dept Neurol & Pathol, Charlestown, MA USA

[20] Massachusetts Gen Hosp, Charlestown, MA USA

[21] Mayo Clin, Dept Neurosci, Jacksonville, FL USA

[22] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[23] Northwestern Univ, Dept Pathol Neuropathol, Northwestern Cognit Neurol & Alzheimer Dis Ctr, Feinberg Sch Med, Chicago, IL 60611 USA

[24] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR USA

[25] Univ Pittsburgh, Dept Pathol Neuropathol, Med Ctr, Pittsburgh, PA USA

[26] Rush Univ, Med Ctr, Dept Pathol Neuropathol, Chicago, IL USA

[27] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL USA

[28] Icahn Sch Med Mt Sinai, Dept Psychiat, Alzheimers Dis Res Ctr, James J Peters VA Med Ctr, New York, NY 10029 USA

[29] Banner Sun Hlth Res Inst, Dept Neuropathol, Sun City, AZ USA

[30] UC Irvine, Dept Neurol, Dept Epidemiol, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA

[31] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[32] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA

[33] Univ Kentucky, Dept Pathol Neuropathol, Lexington, KY USA

[34] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

[35] Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA USA

[36] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA

[37] Univ Washington, Dept Lab Med & Pathol, Sch Med, Seattle, WA USA

[38] Stanford Univ, Dept Pathol, Palo Alto, CA 94304 USA

[39] Univ Hlth Network, Krembil Brain Inst, Lab Med Program, Toronto, ON, Canada

[40] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada

[41] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[42] Med Univ Vienna, Inst Neurol, Vienna, Austria

[43] Washington Univ, Sch Med, Dept Pathol & Immunol, Dept Neurol,Knight Alzheimer Dis Res Ctr, St Louis, MO USA

[44] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[45] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA

[46] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA

[47] Boston Med Ctr, Boston, MA USA

[48] Univ Texas Southwestern Med Sch Dallas, Dept Pathol Neuropathol, Dallas, TX USA

[49] Univ Exeter, Coll Med & Hlth, Exeter, Devon, England

[50] Icahn Sch Med Mt Sinai, Ctr Cognit Hlth, Dept Neurol, New York, NY 10029 USA

来源：

ACTA NEUROPATHOLOGICA | 2022年 / 143卷 / 01期

基金：

英国医学研究理事会;

关键词：

PROGRESSIVE SUPRANUCLEAR PALSY; AGE-RELATED TAUOPATHY; CRYO-EM STRUCTURES; TUMOR-SUPPRESSOR; NEUROFIBRILLARY TANGLES; SENILE-DEMENTIA; RISK LOCI; COGNITIVE IMPAIRMENT; TAU PATHOLOGY; OLDER PERSONS;

D O I：

10.1007/s00401-021-02379-z

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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-beta (A beta) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and 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. 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.

引用

页码：33 / 53

页数：21

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