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.