Disease‐Associated Mutations of TREM2 Alter the Processing of N‐Linked Oligosaccharides in the Golgi Apparatus

Ji‐Seon Park, In Jung Ji, Hyun Joo An, Min‐Ji Kang, Sang‐Wook Kang, Dong‐Hou Kim, Seung‐Yong Yoon

The triggering receptor expressed on myeloid cells-2 (TREM2) is an immune-modulatory receptor involved in phagocytosis and inflammation. Mutations of Q33X, Y38C, and T66M cause Nasu-Hakola disease (NHD) which is characterized by early onset dementia and bone cysts. A recent, genome-wide association study (GWAS) also revealed that single nucleotide polymorphism (SNP) of TREM2, such as R47H, increased the risk of Alzheimer's disease (AD) similar to ApoE4. However, how these mutations affect the trafficking of TREM2 which may affect the normal functions of TREM2, was not known. In our study we show that TREM2 with NHD mutations are impaired in the glycosylation with complex oligosaccharides in the Golgi apparatus, in the trafficking to plasma membrane and further processing by γ-secretase. Although R47H mutation in AD affected the glycosylation and normal trafficking of TREM2 less, the detailed pattern of glycosylated TREM2 differs from that of the wild type, thus suggesting that precise regulation of TREM2 glycosylation is impaired when arginine at 47 is mutated to histidine. Our results suggest that the impaired glycosylation and trafficking of TREM2 from ER/Golgi to plasma membrane by mutations may inhibit its normal functions in the plasma membrane, which may contribute to the disease.