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.