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

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Genome-wide association study and functional validation implicates JADE1 in tauopathy
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2021-11-01 , DOI: 10.1007/s00401-021-02379-z
Kurt Farrell _{1,

2,

3} , SoongHo Kim _{1,

2,

3} , Natalia Han _{1,

2,

3} , Megan A Iida _{1,

2,

3} , Elias M Gonzalez ₄ , Marcos Otero-Garcia ₅ , Jamie M Walker ₆ , Timothy E Richardson ₆ , Alan E Renton _{2,

7} , Shea J Andrews _{2,

7} , Brian Fulton-Howard _{2,

7} , Jack Humphrey _{2,

7} , Ricardo A Vialle _{2,

7} , Kathryn R Bowles ₇ , Katia de Paiva Lopes _{2,

7} , Kristen Whitney _{1,

2,

3} , Diana K Dangoor _{1,

2,

3} , Hadley Walsh _{1,

2,

3} , Edoardo Marcora _{2,

7} , Marco M Hefti ₈ , Alicia Casella _{1,

2,

3} , Cheick T Sissoko _{1,

2,

3} , Manav Kapoor _{2,

7} , Gloriia Novikova _{2,

7} , Evan Udine _{2,

7} , Garrett Wong _{2,

7} , Weijing Tang ₉ , Tushar Bhangale ₁₀ , Julie Hunkapiller ₁₀ , Gai Ayalon ₁₁ , Robert R Graham ₁₂ , Jonathan D Cherry ₁₃ , Etty P Cortes _{1,

2} , Valeriy Y Borukov _{1,

2} , Ann C McKee ₁₃ , Thor D Stein ₁₃ , Jean-Paul Vonsattel ₁₄ , Andy F Teich ₁₄ , Marla Gearing ₁₅ , Jonathan Glass ₁₅ , Juan C Troncoso ₁₆ , Matthew P Frosch ₁₇ , Bradley T Hyman ₁₇ , Dennis W Dickson ₁₈ , Melissa E Murray ₁₈ , Johannes Attems ₁₉ , Margaret E Flanagan ₂₀ , Qinwen Mao ₂₀ , M-Marsel Mesulam ₂₀ , Sandra Weintraub ₂₀ , Randy L Woltjer ₂₁ , Thao Pham ₂₁ , Julia Kofler ₂₂ , Julie A Schneider ₂₃ , Lei Yu ₂₃ , Dushyant P Purohit _{1,

24} , Vahram Haroutunian _{2,

24} , Patrick R Hof ₂ , Sam Gandy _{24,

25} , Mary Sano ₂₄ , Thomas G Beach ₂₆ , Wayne Poon ₂₇ , Claudia H Kawas ₂₈ , María M Corrada ₂₇ , Robert A Rissman ₂₉ , Jeff Metcalf ₂₉ , Sara Shuldberg ₂₉ , Bahar Salehi ₂₉ , Peter T Nelson ₃₀ , John Q Trojanowski ₃₁ , Edward B Lee ₃₁ , David A Wolk ₃₂ , Corey T McMillan ₃₂ , C Dirk Keene ₃₃ , Caitlin S Latimer ₃₃ , Thomas J Montine _{9,

33} , Gabor G Kovacs _{34,

35,

36} , Mirjam I Lutz ₃₆ , Peter Fischer ₃₇ , Richard J Perrin ₃₈ , Nigel J Cairns ₃₉ , Erin E Franklin ₃₈ , Herbert T Cohen ₄₀ , Towfique Raj _{2,

7} , Inma Cobos ₉ , Bess Frost ₄ , Alison Goate _{2,

7} , Charles L White Iii ₄₁ , John F Crary _{1,

2,

3}

Affiliation

Department of Pathology, Neuropathology Brain Bank and Research CoRE, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1194, New York, NY, 10029, USA.
Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Cell Systems and Anatomy, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, USA.
Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pathology, University of Iowa, Iowa City, IA, USA.
Department of Pathology, Stanford University, Palo Alto, USA.
Department of Human Genetics, Genentech, South San Francisco, CA, USA.
Neumora Therapeutics, South San Francisco, CA, USA.
Maze Therapeutics, San Francisco, CA, USA.
Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA.
Department of Pathology and Cell Biology, Department of Neurology, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Pathology, Oregon Health Sciences University, Portland, OR, USA.
Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Department of Psychiatry, Alzheimer's Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neurology, Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.
Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Department of Psychiatry, Danube Hospital, Vienna, Austria.
Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
College of Medicine and Health, University of Exeter, Exeter, UK.
Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA.
Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, USA.

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.

中文翻译：

全基因组关联研究和功能验证表明 JADE1 与 tau 蛋白病有关

原发性年龄相关性 tau 蛋白病 (PART) 是一种神经退行性病变，其特征不同于阿尔茨海默病 (AD)，但也与之重叠。虽然两者都表现出阿尔茨海默型颞叶神经原纤维变性和遗忘性认知障碍，但 PART 的发展独立于淀粉样蛋白 -β (Aβ) 斑块。PART 的发病机制尚不清楚，但有证据表明与促进 tau 病理学的基因和其他保护免受 Aβ 毒性的基因有关。在这里，我们使用 Braak 神经原纤维缠结阶段作为数量性状，对 PART 患者（ n = 647）的尸检队列进行了遗传关联研究。我们发现与 AD 相关的候选基因座有一些显着关联（SLC24A4、MS4A6A、HS3ST1) 和进行性核上性麻痹（MAPT和EIF2AK3）。全基因组关联分析揭示了与 4 号染色体 (rs56405341) 上包含三个基因的基因座中的单核苷酸多态性的新的显着关联，包括 JADE1，它在缠结神经元中被单胞体 RNA-seq 显着上调。使用针对 JADE1 蛋白的抗血清进行的免疫组织化学研究表明，尸检大脑中的 tau 聚集体定位于具有四个微管结合域重复 (4R) 亚型和混合 3R/4R，但不完全是 3R。死后人类 PART 脑组织的免疫共沉淀揭示了 JADE1 蛋白与四个缺乏 N 末端插入片段的重复 tau (0N4R) 的特异性结合。最后，击倒果蝇JADE1 同系物犀牛( rno ) 在人源化 0N4R 突变体 tau 敲入模型中增强了 tau 诱导的体内毒性和细胞凋亡，通过粗眼表型和果蝇大脑中的末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 进行量化。总之，这些发现表明 PART 具有与 AD 和其他 tau 病部分重叠的遗传结构，并表明 JADE1 作为神经原纤维变性调节剂的新作用。

更新日期：2021-11-02

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