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    Acta neuropathologica. 2021 Nov 1. doi: 10.1007/s00401-021-02379-z. pii: 10.1007/s00401-021-02379-z
    Genome-wide association study and functional validation implicates JADE1 in tauopathy.
    Farrell K1,  Kim S2,  Han N3,  Iida MA4,  Gonzalez EM5,  Otero-Garcia M6,  Walker JM7,  Richardson TE8,  Renton AE9,  Andrews SJ10,  Fulton-Howard B11,  Humphrey J12,  Vialle RA13,  Bowles KR14,  de Paiva Lopes K15,  Whitney K16,  Dangoor DK17,  Walsh H18,  Marcora E19,  Hefti MM20,  Casella A21,  Sissoko CT22,  Kapoor M23,  Novikova G24,  Udine E25,  Wong G26,  Tang W27,  Bhangale T28,  Hunkapiller J29,  Ayalon G30,  Graham RR31,  Cherry JD32,  Cortes EP33,  Borukov VY34,  McKee AC35,  Stein TD36,  Vonsattel JP37,  Teich AF38,  Gearing M39,  Glass J40,  Troncoso JC41,  Frosch MP42,  Hyman BT43,  Dickson DW44,  Murray ME45,  Attems J46,  Flanagan ME47,  Mao Q48,  Mesulam MM49,  Weintraub S50,  Woltjer RL51,  Pham T52,  Kofler J53,  Schneider JA54,  Yu L55,  Purohit DP56,  Haroutunian V57,  Hof PR58,  Gandy S59,  Sano M60,  Beach TG61,  Poon W62,  Kawas CH63,  Corrada MM64,  Rissman RA65,  Metcalf J66,  Shuldberg S67,  Salehi B68,  Nelson PT69,  Trojanowski JQ70,  Lee EB71,  Wolk DA72,  McMillan CT73,  Keene CD74,  Latimer CS75,  Montine TJ76,  Kovacs GG77,  Lutz MI78,  Fischer P79,  Perrin RJ80,  Cairns NJ81,  Franklin EE82,  Cohen HT83,  Raj T84,  Cobos I85,  Frost B86,  Goate A87,  White Iii CL88,  Crary JF89
    Author information
    1Department 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.
    2Department 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.
    3Department 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.
    4Department 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.
    5Department 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.
    6Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, USA.
    7Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
    8Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
    9Nash 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.
    10Nash 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.
    11Nash 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.
    12Nash 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.
    13Nash 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.
    14Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    15Nash 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.
    16Department 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.
    17Department 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.
    18Department 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.
    19Nash 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.
    20Department of Pathology, University of Iowa, Iowa City, IA, USA.
    21Department 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.
    22Department 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.
    23Nash 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.
    24Nash 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.
    25Nash 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.
    26Nash 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.
    27Department of Pathology, Stanford University, Palo Alto, USA.
    28Department of Human Genetics, Genentech, South San Francisco, CA, USA.
    29Department of Human Genetics, Genentech, South San Francisco, CA, USA.
    30Neumora Therapeutics, South San Francisco, CA, USA.
    31Maze Therapeutics, San Francisco, CA, USA.
    32Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA.
    33Department 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.
    34Department 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.
    35Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA.
    36Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA.
    37Department 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.
    38Department 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.
    39Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA.
    40Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA.
    41Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
    42Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA.
    43Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA.
    44Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
    45Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
    46Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
    47Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    48Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    49Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    50Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    51Department of Pathology, Oregon Health Sciences University, Portland, OR, USA.
    52Department of Pathology, Oregon Health Sciences University, Portland, OR, USA.
    53Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
    54Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
    55Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
    56Department 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.
    57Nash 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.
    58Nash 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.
    59Department of Psychiatry, Alzheimer's Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    60Department of Psychiatry, Alzheimer's Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    61Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
    62Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
    63Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
    64Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
    65Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
    66Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
    67Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
    68Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
    69Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
    70Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    71Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    72Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    73Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
    74Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.
    75Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.
    76Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.
    77Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
    78Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    79Department of Psychiatry, Danube Hospital, Vienna, Austria.
    80Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
    81College of Medicine and Health, University of Exeter, Exeter, UK.
    82Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
    83Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA.
    84Nash 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.
    85Department of Pathology, Stanford University, Palo Alto, USA.
    86Department 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.
    87Nash 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.
    88Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, USA.
    89Department 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. john.crary@mountsinai.org.
    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.


    © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

    Publikations ID: 34719765
    Quelle: öffnen
     
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