2. Academic Validation
  3. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

  • Sci Transl Med. 2014 Jul 2;6(243):243ra86. doi: 10.1126/scitranslmed.3009093.
Gernot Kleinberger 1,  Yoshinori Yamanishi 2,  Marc Suárez-Calvet 3,  Eva Czirr 4,  Ebba Lohmann 5,  Elise Cuyvers 6,  Hanne Struyfs 7,  Nadine Pettkus 8,  Andrea Wenninger-Weinzierl 9,  Fargol Mazaheri 9,  Sabina Tahirovic 9,  Alberto Lleó 10,  Daniel Alcolea 10,  Juan Fortea 10,  Michael Willem 8,  Sven Lammich 8,  José L Molinuevo 11,  Raquel Sánchez-Valle 11,  Anna Antonell 11,  Alfredo Ramirez 12,  Michael T Heneka 13,  Kristel Sleegers 6,  Julie van der Zee 6,  Jean-Jacques Martin 14,  Sebastiaan Engelborghs 15,  Asli Demirtas-Tatlidede 16,  Henrik Zetterberg 17,  Christine Van Broeckhoven 6,  Hakan Gurvit 16,  Tony Wyss-Coray 18,  John Hardy 19,  Marco Colonna 2,  Christian Haass 20
Affiliations

Affiliations

  • 1 Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
  • 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
  • 7 Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
  • 8 Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
  • 9 German Center for Neurodegenerative Diseases (DZNE), Munich, 80336 Munich, Germany.
  • 10 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.
  • 11 Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, 08036 Barcelona, Spain.
  • 12 Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 13 Universitätsklinikum Bonn, Neurology, 53127 Bonn, Germany. German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
  • 14 Antwerp Biobank, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
  • 15 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.
  • 16 Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey.
  • 17 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.
  • 18 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.
  • 19 Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
  • 20 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.
PMID: 24990881 DOI: 10.1126/scitranslmed.3009093
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.

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