title: TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.
abstract: Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamanishi
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany. Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain. Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, 28031 Madrid, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Czirr
authors.affiliation: Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany. German Center for Neurodegenerative Diseases (DZNE), Tübingen, 72076 Tübingen, Germany.
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Elise
authors.initials: E
authors.lastname: Cuyvers
authors.affiliation: Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Struyfs
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Pettkus
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wenninger-Weinzierl
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany.
authors.forename: Fargol
authors.initials: F
authors.lastname: Mazaheri
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain. Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, 28031 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain. Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, 28031 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcolea
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain. Center for Networked Biomedical Research for Neurodegenerative Diseases, CIBERNED, 28031 Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Lammich
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Antonell
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Universitätsklinikum Bonn, Neurology, 53127 Bonn, Germany. German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Antwerp Biobank, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium. Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA), Middelheim and Hoge Beuken, 2020 Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey.
authors.forename: Asli
authors.initials: A
authors.lastname: Demirtas-Tatlidede
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden. Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gurvit
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA. Neuroscience IDP Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany. christian.haass@dzne.lmu.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human