title: Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms.
abstract: Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer's risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.
authors.affiliation: Molecular Microbiology and Microbial Pathogenesis Program, Washington University School of Medicine, St. Louis, United States.|Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kober
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Alexander-Brett
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, United States.
authors.forename: Celeste M
authors.identifier: 0000-0002-6854-5547
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, United States.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, United States.|Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States.
authors.forename: Thomas J
authors.identifier: 0000-0002-6871-6676
authors.initials: TJ
authors.lastname: Brett
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D050505:Mutant Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; biophysics; crystallography; human; inflammation; microglia; mouse; neuroscience; structural biology