@article{bb590a00c9ce4c1bb5c733a237a0353c,
title = "TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration",
abstract = "Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.",
author = "Manling Xie and Liu, {Yong U.} and Shunyi Zhao and Lingxin Zhang and Bosco, {Dale B.} and Pang, {Yuan Ping} and Jun Zhong and Udit Sheth and Martens, {Yuka A.} and Na Zhao and Liu, {Chia Chen} and Yongxian Zhuang and Liewei Wang and Dickson, {Dennis W.} and Mattson, {Mark P.} and Guojun Bu and Wu, {Long Jun}",
note = "Funding Information: We thank M. Colonna (Washington University) for providing Trem2-KO mice; R.L. Klein (Louisiana State University) for providing AAV virus; V.A. Lennon (Mayo Clinic Rochester) for thoughtful discussion and manuscript editing; W. Rossoll (Mayo Clinic Florida) for insightful suggestions; A.J. Johnson (Mayo Clinic Rochester), Y. Zhu (Mayo Clinic Rochester) and K.D. Pavelko (Mayo Clinic Rochester Immune Monitoring Core) for assistance with CyTOF sample preparation and data analysis; A. Pandey (Mayo Clinic Rochester) and the Mayo Clinic Proteomics Core (a shared resource of the Mayo Clinic Cancer Center) for LC–MS/MS experiment and data analysis; C. Howe and B. Clarkson (Mayo Clinic Rochester) for providing iPSC-derived neurons and R.M. Weinshilboum (Mayo Clinic Rochester) for assistance with biochemistry experiments. The current study is supported by NIH grants R21AG064159 and R01NS088627 to L.-J.W., R01AG066395 to G.B. and N.Z. and U19AG069701 to G.B., Y.A.M., N.Z., C.-C.L., D.W.D. and L.-J.W. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jan,
doi = "10.1038/s41593-021-00975-6",
language = "English (US)",
volume = "25",
pages = "26--38",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "1",
}