[en] 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.
Disciplines :
Neurology
Author, co-author :
Kleinberger, Gernot; Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany
Yamanishi, Yoshinori; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Suárez-Calvet, Marc; 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
Czirr, Eva; 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
Lohmann, Ebba; 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
Cuyvers, Elise; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Struyfs, Hanne; Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Pettkus, Nadine; Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany
Wenninger-Weinzierl, Andrea; German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany
Mazaheri, Fargol; German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany
Tahirovic, Sabina; German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany
Lleó, Alberto; 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
Alcolea, Daniel; 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
Fortea, Juan; 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
Willem, Michael; Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany
Lammich, Sven; Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany
Molinuevo, José L; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain
Sánchez-Valle, Raquel; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain
Antonell, Anna; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain
Ramirez, Alfredo; Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
HENEKA, Michael ; Universitätsklinikum Bonn, Neurology, 53127 Bonn, Germany. German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Sleegers, Kristel; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
van der Zee, Julie; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Martin, Jean-Jacques; Antwerp Biobank, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Engelborghs, Sebastiaan; 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
Demirtas-Tatlidede, Asli; Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey
Zetterberg, Henrik; 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
Van Broeckhoven, Christine; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Gurvit, Hakan; Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey
Wyss-Coray, Tony; 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
Hardy, John; Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK
Colonna, Marco; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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