title: Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models.
abstract: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease.
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Dora
authors.initials: D
authors.lastname: Games
authors.affiliation: Department of Neurosciences and.
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.affiliation: Department of Neurosciences and.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Neurosciences and.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences and.
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.affiliation: Department of Neurosciences and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Neurosciences and.
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.affiliation: Department of Neurosciences and.
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.affiliation: Department of Neurosciences and.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sacayon
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Seubert
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Robin
authors.initials: R
authors.lastname: Barbour
authors.affiliation: Prothena Biosciences, South San Francisco, California 94080, and.
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.affiliation: Department of Neurosciences and Department of Pathology, University of California, San Diego, La Jolla, California 92093 emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000276:immunology* / Q000628:therapy*; D020734:Parkinsonian Disorders / Q000276:immunology* / Q000628:therapy*; D014018:Tissue Distribution; D016896:Treatment Outcome; D051844:alpha-Synuclein / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D051844:alpha-Synuclein
keywords: Parkinson's disease; calpain; immunotherapy; α-synuclein; α-synuclein propagation; α-synuclein truncation