title: Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson's disease.
abstract: The protein α-synuclein (α-Syn) has a central role in the pathogenesis of Parkinson's disease (PD) and immunotherapeutic approaches targeting this molecule have shown promising results. In this study, novel antibodies were generated against specific peptides from full length human α-Syn and evaluated for effectiveness in ameliorating α-Syn-induced cell death and behavioral deficits in an AAV-α-Syn expressing rat model of PD. Fisher 344 rats were injected with rAAV vector into the right substantia nigra (SN), while control rats received an AAV vector expressing green fluorescent protein (GFP). Beginning one week after injection of the AAV-α-Syn vectors, rats were treated intraperitoneally with either control IgG or antibodies against the N-terminal (AB1), or central region (AB2) of α-Syn. An unbiased stereological estimation of TH+, NeuN+, and OX6 (MHC-II) immunostaining revealed that the α-Syn peptide antibodies (AB1 and AB2) significantly inhibited α-Syn-induced dopaminergic cell (DA) and NeuN+ cell loss (one-way ANOVA (F (3, 30) = 5.8, p = 0.002 and (F (3, 29) = 7.92, p = 0.002 respectively), as well as decreasing the number of activated microglia in the ipsilateral SN (one-way ANOVA F = 14.09; p = 0.0003). Antibody treated animals also had lower levels of α-Syn in the ipsilateral SN (one-way ANOVA F (7, 37) = 9.786; p = 0.0001) and demonstrated a partial intermediate improvement of the behavioral deficits. Our data suggest that, in particular, an α-Syn peptide antibody against the N-terminal region of the protein can protect against DA neuron loss and, to some extent behavioral deficits. As such, these results may be a potential therapeutic strategy for halting the progression of PD.
authors: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America.
authors: Md
authors: M
authors: Shahaduzzaman
authors: Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America; USF-Health Byrd Alzheimer's Institute University of South Florida, Tampa, Florida, 33612, United States of America.
authors: Kevin
authors: K
authors: Nash
authors: James A. Haley Veterans Affairs Hospital, Research Service, Tampa, Florida, 33612, United States of America.
authors: Charles
authors: C
authors: Hudson
authors: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America.
authors: Masroor
authors: M
authors: Sharif
authors: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America.
authors: Bethany
authors: B
authors: Grimmig
authors: USF-Health Byrd Alzheimer's Institute University of South Florida, Tampa, Florida, 33612, United States of America.
authors: Xiaoyang
authors: X
authors: Lin
authors: USF-Health Byrd Alzheimer's Institute University of South Florida, Tampa, Florida, 33612, United States of America.
authors: Ge
authors: G
authors: Bai
authors: USF-Health Byrd Alzheimer's Institute University of South Florida, Tampa, Florida, 33612, United States of America.
authors: Hui
authors: H
authors: Liu
authors: Dept. of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America; Center for Molecular Delivery, University of South Florida, Tampa, Florida, 33620, United States of America.
authors: Kenneth E
authors: KE
authors: Ugen
authors: USF-Health Byrd Alzheimer's Institute University of South Florida, Tampa, Florida, 33612, United States of America; Dept. of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, 33612, United States of America.
authors: Chuanhai
authors: C
authors: Cao
authors: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America; Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, United States of America; James A. Haley Veterans Affairs Hospital, Research Service, Tampa, Florida, 33612, United States of America.
authors: Paula C
authors: PC
authors: Bickford
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D000229:Dependovirus; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007274:Injections, Intraperitoneal; D010300:Parkinson Disease / Q000188:drug therapy* / Q000276:immunology*; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000009:adverse effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins