title: Unveiling the role of the pesticides paraquat and rotenone on α-synuclein fibrillation in vitro.
abstract: Epidemiological data have suggested that exposure to environmental toxins might be associated with the etiology of Parkinson's disease (PD). In this context, certain agrochemicals are able to induce Parkinsonism in different animal models via the inhibition of mitochondrial complex I, which leads to an increase in both oxidative stress and the death of nigrostriatal neurons. Additionally, in vitro experiments have indicated that pesticides are capable of accelerating the fibrillation of the presynaptic protein α-synuclein (aS) by binding directly to the protein. However, the molecular details of these interactions are poorly understood. In the present work we demonstrate that paraquat and rotenone, two agrochemicals that lead to a Parkinsonian phenotype in vivo, bind to aS via solvent effects rather than through specific interactions. In fact, these compounds produced no significant effects on aS fibrillation under physiological concentrations of NaCl. NMR data suggest that paraquat interacts with the C-terminal domain of the disordered aS monomer. This interaction was markedly reduced in the presence of NaCl, presumably due to the disruption of electrostatic interactions between the protein and paraquat. Interestingly, the effects produced by short-term incubation of paraquat with aS on the protein conformation resembled those produced by incubating the protein with NaCl alone. Taken together, our data indicate that the effects of these agrochemicals on PD cannot be explained via direct interactions with aS, reinforcing the idea that the role of these compounds in PD is limited to the inhibition of mitochondrial complex I and/or the up-regulation of aS.
authors.affiliation: Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
authors.forename: Maurício Guilherme Valente
authors.initials: MG
authors.lastname: Maturana
authors.affiliation: Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
authors.forename: Anderson Sá
authors.initials: AS
authors.lastname: Pinheiro
authors.affiliation: Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
authors.forename: Theo Luiz Ferraz
authors.initials: TL
authors.lastname: de Souza
authors.affiliation: Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil. Electronic address: follmer@iq.ufrj.br.
authors.forename: Cristian
authors.initials: C
authors.lastname: Follmer
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D046529:Microscopy, Electron, Transmission; D019906:Nuclear Magnetic Resonance, Biomolecular; D010269:Paraquat / Q000494:pharmacology*; D010575:Pesticides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011868:Radioisotopes / Q000493:pharmacokinetics; D012402:Rotenone / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D010575:Pesticides; D011868:Radioisotopes; D051844:alpha-Synuclein; D012402:Rotenone; D012965:Sodium Chloride; D010269:Paraquat
keywords: Fibrils; Paraquat; Parkinson's disease; Rotenone; α-Synuclein