title: Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Park
authors.forename: In Jung
authors.initials: IJ
authors.lastname: Ji
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: An
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kang
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009844:Oligosaccharides / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D013344:Subacute Sclerosing Panencephalitis / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; Nasu-Hakola disease; TREM2; glycosylation; trafficking