TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

被引：596

作者：

Kleinberger, Gernot ^{[1
,2
]}

Yamanishi, Yoshinori ^{[3
]}

Suarez-Calvet, Marc ^{[1
,4
,5
]}

Czirr, Eva ^{[6
,7
]}

Lohmann, Ebba ^{[8
,9
,10
]}

Cuyvers, Elise ^{[11
,12
]}

Struyfs, Hanne ^{[13
]}

Pettkus, Nadine ^{[1
]}

Wenninger-Weinzierl, Andrea ^{[14
]}

Mazaheri, Fargol ^{[14
]}

Tahirovic, Sabina ^{[14
]}

Lleo, Alberto ^{[4
,5
]}

Alcolea, Daniel ^{[4
,5
]}

Fortea, Juan ^{[4
,5
]}

Willem, Michael ^{[1
]}

Lammich, Sven ^{[1
]}

Molinuevo, Jose L.

Sanchez-Valle, Raquel ^{[15
]}

Antonell, Anna ^{[15
]}

Ramirez, Alfredo ^{[16
,17
,18
]}

Heneka, Michael T. ^{[19
,20
]}

Sleegers, Kristel ^{[11
,12
]}

van der Zee, Julie ^{[11
,12
]}

Martin, Jean-Jacques ^{[21
]}

Engelborghs, Sebastiaan ^{[13
,22
,23
]}

Demirtas-Tatlidede, Asli ^{[8
]}

Zetterberg, Henrik ^{[24
,25
]}

Van Broeckhoven, Christine ^{[11
,12
]}

Gurvit, Hakan ^{[8
]}

Wyss-Coray, Tony ^{[7
,26
]}

Hardy, John ^{[25
]}

Colonna, Marco

Haass, Christian ^{[1
,2
,14
]}

机构：

[1] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany

[2] Munich Cluster Syst Neurol SyNergy, D-80336 Munich, Germany

[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[4] Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain

[5] CIBERNED, Ctr Networked Biomed Res Neurodegenerat Dis, Madrid 28031, Spain

[6] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[7] Vet Adm Palo Alto Hlth Care Syst, Ctr Tissue Regenerat Repair & Restorat, Palo Alto, CA 94304 USA

[8] Istanbul Univ, Istanbul Fac Med, Dept Neurol, Behav Neurol & Movement Disorders Unit, TR-34093 Istanbul, Turkey

[9] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, D-72076 Tubingen, Germany

[10] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany

[11] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium

[12] Univ Antwerp, Inst Born Bunge, Lab Neurogenet, B-2610 Antwerp, Belgium

[13] Univ Antwerp, Reference Ctr Biol Markers Dementia, Inst Born Bunge, Lab Neurochem & Behav, B-2610 Antwerp, Belgium

[14] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany

[15] ICN Hosp Clin & Univ, Neurol Serv, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona 08036, Spain

[16] Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany

[17] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany

[18] Univ Klinikum Bonn, D-53127 Bonn, Germany

[19] German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany

[20] Univ Antwerp, Inst Born Bunge, Antwerp Biobank, B-2610 Antwerp, Belgium

[21] Hosp Network Antwerp ZNA, Dept Neurol, B-2020 Antwerp, Belgium

[22] Hosp Network Antwerp ZNA, Memory Clin, B-2020 Antwerp, Belgium

[23] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden

[24] UCL, Inst Neurol, Reta Lila Weston Labs, London WC1N 3BG, England

[25] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[26] Stanford Univ, Sch Med, Neurosci IDP Program, Stanford, CA 94305 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 243期

基金：

欧洲研究理事会;

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; AMYLOID PRECURSOR PROTEIN; RISK-FACTOR; INTRAMEMBRANE PROTEOLYSIS; ALZHEIMERS-DISEASE; PROGRANULIN LEVELS; CUTTING EDGE; RECEPTOR; DEMENTIA; VARIANT;

D O I：

10.1126/scitranslmed.3009093

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：12

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