title: Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration.
abstract: Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hien T
authors.initials: HT
authors.lastname: Tran
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Charlotte Hiu-Yan
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Kelvin C
authors.initials: KC
authors.lastname: Luk
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. Electronic address: vmylee@upenn.edu.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D007167:Immunotherapy / Q000379:methods; D020961:Lewy Body Disease / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D051844:alpha-Synuclein / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D051844:alpha-Synuclein