PT  - JOURNAL ARTICLE
AU  - Kleinberger, Gernot
AU  - Yamanishi, Yoshinori
AU  - Suárez-Calvet, Marc
AU  - Czirr, Eva
AU  - Lohmann, Ebba
AU  - Cuyvers, Elise
AU  - Struyfs, Hanne
AU  - Pettkus, Nadine
AU  - Wenninger-Weinzierl, Andrea
AU  - Mazaheri, Fargol
AU  - Tahirovic, Sabina
AU  - Lleó, Alberto
AU  - Alcolea, Daniel
AU  - Fortea, Juan
AU  - Willem, Michael
AU  - Lammich, Sven
AU  - Molinuevo, José L.
AU  - Sánchez-Valle, Raquel
AU  - Antonell, Anna
AU  - Ramirez, Alfredo
AU  - Heneka, Michael T.
AU  - Sleegers, Kristel
AU  - van der Zee, Julie
AU  - Martin, Jean-Jacques
AU  - Engelborghs, Sebastiaan
AU  - Demirtas-Tatlidede, Asli
AU  - Zetterberg, Henrik
AU  - Van Broeckhoven, Christine
AU  - Gurvit, Hakan
AU  - Wyss-Coray, Tony
AU  - Hardy, John
AU  - Colonna, Marco
AU  - Haass, Christian
TI  - TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
AID  - 10.1126/scitranslmed.3009093
DP  - 2014 Jul 02
TA  - Science Translational Medicine
PG  - 243ra86--243ra86
VI  - 6
IP  - 243
4099  - http://stm.sciencemag.org/content/6/243/243ra86.short
4100  - http://stm.sciencemag.org/content/6/243/243ra86.full
AB  - 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.