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

Autor:	Farrell K; 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., Kim S; 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., Han N; 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., Iida MA; 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., Gonzalez EM; 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., Otero-Garcia M; Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, USA., Walker JM; Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA., Richardson TE; Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA., Renton AE; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Andrews SJ; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fulton-Howard B; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Humphrey J; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Vialle RA; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bowles KR; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., de Paiva Lopes K; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Whitney K; 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., Dangoor DK; 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., Walsh H; 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., Marcora E; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Hefti MM; Department of Pathology, University of Iowa, Iowa City, IA, USA., Casella A; 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., Sissoko CT; 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., Kapoor M; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Novikova G; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Udine E; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wong G; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Tang W; Department of Pathology, Stanford University, Palo Alto, USA., Bhangale T; Department of Human Genetics, Genentech, South San Francisco, CA, USA., Hunkapiller J; Department of Human Genetics, Genentech, South San Francisco, CA, USA., Ayalon G; Neumora Therapeutics, South San Francisco, CA, USA., Graham RR; Maze Therapeutics, San Francisco, CA, USA., Cherry JD; Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA., Cortes EP; 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., Borukov VY; 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., McKee AC; Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA., Stein TD; Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA., Vonsattel JP; 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., Teich AF; 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., Gearing M; Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA., Glass J; Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA., Troncoso JC; Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Frosch MP; Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA., Hyman BT; Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Murray ME; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Attems J; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Flanagan ME; Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Mao Q; Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Mesulam MM; Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Weintraub S; Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Woltjer RL; Department of Pathology, Oregon Health Sciences University, Portland, OR, USA., Pham T; Department of Pathology, Oregon Health Sciences University, Portland, OR, USA., Kofler J; Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Schneider JA; Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA., Yu L; Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA., Purohit DP; 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.; 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., Haroutunian V; 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 Psychiatry, Alzheimer's Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Hof PR; 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., Gandy S; 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., Sano M; 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., Beach TG; Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA., Poon W; Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA., Kawas CH; Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA., Corrada MM; Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA., Rissman RA; Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA., Metcalf J; Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA., Shuldberg S; Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA., Salehi B; Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA., Nelson PT; Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA., Trojanowski JQ; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lee EB; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Wolk DA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., McMillan CT; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Keene CD; Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA., Latimer CS; Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA., Montine TJ; Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.; Department of Pathology, Stanford University, Palo Alto, USA., Kovacs GG; 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., Lutz MI; Institute of Neurology, Medical University of Vienna, Vienna, Austria., Fischer P; Department of Psychiatry, Danube Hospital, Vienna, Austria., Perrin RJ; Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA., Cairns NJ; College of Medicine and Health, University of Exeter, Exeter, UK., Franklin EE; Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA., Cohen HT; Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA., Raj T; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Cobos I; Department of Pathology, Stanford University, Palo Alto, USA., Frost B; 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., Goate A; 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 Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., White Iii CL; Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, USA., Crary JF; 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. john.crary@mountsinai.org.; 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. john.crary@mountsinai.org.; Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. john.crary@mountsinai.org.
Jazyk:	angličtina
Zdroj:	Acta neuropathologica [Acta Neuropathol] 2022 Jan; Vol. 143 (1), pp. 33-53. Date of Electronic Publication: 2021 Nov 01.
DOI:	10.1007/s00401-021-02379-z
Abstrakt:	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.)
Databáze:	MEDLINE
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