title: Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission.
abstract: Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.
authors.affiliation: Department of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Bae
authors.forename: He-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Ho
authors.forename: Eun-Bi
authors.initials: EB
authors.lastname: Park
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Yang
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000682:Amyloid / Q000378:metabolism / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D002850:Chromatography, Gel; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive; D020961:Lewy Body Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: C491049:Aif1 protein, mouse; D000682:Amyloid; D000906:Antibodies; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D051242:Caveolin 1; D017077:Culture Media, Conditioned; D016207:Cytokines; D008840:Microfilament Proteins; D010982:Platelet-Derived Growth Factor; D051844:alpha-Synuclein; D002402:Cathepsin D; D010751:Phosphopyruvate Hydratase