RT Journal Article SR Electronic T1 TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis JF Science Translational Medicine FD American Association for the Advancement of Science SP 243ra86 OP 243ra86 DO 10.1126/scitranslmed.3009093 VO 6 IS 243 A1 Kleinberger, Gernot A1 Yamanishi, Yoshinori A1 Suárez-Calvet, Marc A1 Czirr, Eva A1 Lohmann, Ebba A1 Cuyvers, Elise A1 Struyfs, Hanne A1 Pettkus, Nadine A1 Wenninger-Weinzierl, Andrea A1 Mazaheri, Fargol A1 Tahirovic, Sabina A1 Lleó, Alberto A1 Alcolea, Daniel A1 Fortea, Juan A1 Willem, Michael A1 Lammich, Sven A1 Molinuevo, José L. A1 Sánchez-Valle, Raquel A1 Antonell, Anna A1 Ramirez, Alfredo A1 Heneka, Michael T. A1 Sleegers, Kristel A1 van der Zee, Julie A1 Martin, Jean-Jacques A1 Engelborghs, Sebastiaan A1 Demirtas-Tatlidede, Asli A1 Zetterberg, Henrik A1 Van Broeckhoven, Christine A1 Gurvit, Hakan A1 Wyss-Coray, Tony A1 Hardy, John A1 Colonna, Marco A1 Haass, Christian YR 2014 UL http://stm.sciencemag.org/content/6/243/243ra86.abstract 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.