title: ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD's etiology is unknown, α-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction. Increasing experimental evidence indicates that ER stress is involved in PD, however most of the described results employed cultured cell lines and genetically modified animal models. In this study, we developed a new ER stress rat model employing the well-known ER stressor tunicamycin (Tm). To evaluate if ER stress was able to induce PD features, we performed an intranigral injection of Tm (0.1 μg/cerebral hemisphere) and animals (male Wistar rats) were analyzed 7 days post injection. The classical 6-OHDA neurotoxin model (1 μg/cerebral hemisphere) was used as an established positive control for PD. We show that Tm injection induced locomotor impairment, dopaminergic neurons death, and activation of astroglia. In addition, we observed an extensive α-synuclein oligomerization in SNpc of Tm-injected animals when compared with DMSO-injected controls. Finally, both Tm and 6-OHDA treated animals presented increased levels of ER stress markers. Taken together, these findings show for the first time that the ER stressor Tm recapitulates some of the phenotypic characteristics observed in rodent models of PD, reinforcing the concept that ER stress could be an important contributor to the pathophysiology of PD. Therefore, we propose the intranigral Tm injection as a new ER stress-based model for the study of PD in vivo.
authors.affiliation: Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Av. Francisco H. dos Santos, s/n, Curitiba, 81531-980, Paraná, Brazil.
authors.forename: Valentín
authors.initials: V
authors.lastname: Cóppola-Segovia
authors.affiliation: Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Av. Francisco H. dos Santos, s/n, Curitiba, 81531-980, Paraná, Brazil.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Cavarsan
authors.affiliation: Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Av. Francisco H. dos Santos, s/n, Curitiba, 81531-980, Paraná, Brazil.
authors.forename: Flavia G
authors.initials: FG
authors.lastname: Maia
authors.affiliation: Department of Physiology, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: Anete C
authors.initials: AC
authors.lastname: Ferraz
authors.affiliation: Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Av. Francisco H. dos Santos, s/n, Curitiba, 81531-980, Paraná, Brazil.
authors.forename: Lia S
authors.initials: LS
authors.lastname: Nakao
authors.affiliation: Department of Physiology, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: Marcelo Ms
authors.initials: MM
authors.lastname: Lima
authors.affiliation: Laboratory of Neurobiology and Redox Pathology, Department of Basic Pathology, Setor de Ciências Biológicas, Universidade Federal do Paraná, Av. Francisco H. dos Santos, s/n, Curitiba, 81531-980, Paraná, Brazil. smzanata@ufpr.br.
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Zanata
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014415:Tunicamycin / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D014415:Tunicamycin
keywords: ER-stress; Parkinson’s disease; Tunicamycin; α-Synuclein oligomerization