Park Ji-Seon, Ji In Jung, An Hyun Joo, Kang Min-Ji, Kang Sang-Wook, Kim Dong-Hou, Yoon Seung-Yong
Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Brain Science, University of Ulsan College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Republic of Korea; Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
Traffic. 2015 May;16(5):510-8. doi: 10.1111/tra.12264. Epub 2015 Feb 24.
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 of dementia and bone cysts. A recent, genome-wide association study also revealed that single nucleotide polymorphism 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 this 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 endoplasmic reticulum/Golgi to plasma membrane by mutations may inhibit its normal functions in the plasma membrane, which may contribute to the disease.
髓系细胞触发受体2（TREM2）是一种参与吞噬作用和炎症反应的免疫调节受体。Q33X、Y38C和T66M突变会导致纳苏-哈科拉病（NHD），其特征为早发性痴呆和骨囊肿。最近一项全基因组关联研究还发现，TREM2的单核苷酸多态性，如R47H，会增加患阿尔茨海默病（AD）的风险，这与载脂蛋白E4（ApoE4）的作用类似。然而，这些突变如何影响TREM2的转运，进而可能影响TREM2的正常功能，此前并不清楚。在本研究中，我们发现带有NHD突变的TREM2在高尔基体中与复合寡糖的糖基化、向质膜的转运以及γ-分泌酶的进一步加工过程中均受到损害。尽管AD中的R47H突变对TREM2糖基化和正常转运的影响较小，但糖基化TREM2的详细模式与野生型不同，这表明当47位的精氨酸突变为组氨酸时，TREM2糖基化的精确调控受到损害。我们的研究结果表明，突变导致TREM2从内质网/高尔基体到质膜的糖基化和转运受损，可能会抑制其在质膜中的正常功能，这可能与疾病的发生有关。
