title: Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity.
abstract: Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Villar-Piqué
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Tomás
authors.initials: T
authors.lastname: Lopes da Fonseca
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sant'Anna
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Éva Mónika
authors.initials: ÉM
authors.lastname: Szegö
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, 37077 Goettingen, Germany.
authors.forename: Luis
authors.initials: L
authors.lastname: Fonseca-Ornelas
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pinho
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Anita
authors.initials: A
authors.lastname: Carija
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Masaracchia
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich, Germany; German Research School for Simulation Sciences, Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Enrique
authors.initials: E
authors.lastname: Abad Gonzalez
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich, Germany; Department of Oncology, Hematology, and Stem Cell Transplantation, Medical School, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Max Planck Laboratory for Structural Biology, Chemistry, and Molecular Biophysics of Rosario, Universidad Nacional de Rosario, Ocampo y Esmeralda, S2002LRK Rosario, Argentina; Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario UNR-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Rosario, Ocampo y Esmeralda, S2002LRK Rosario, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, 21941-901 Rio de Janeiro, Brazil.
authors.forename: Debora
authors.initials: D
authors.lastname: Foguel
authors.affiliation: European Neuroscience Institute, 37077 Goettingen, Germany.
authors.forename: Ira
authors.initials: I
authors.lastname: Milosevic
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie, 37077 Goettingen, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, 37075 Goettingen, Germany; Department of Neurology, University Medicine Göttingen, 37073 Goettingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medicine Göttingen, 37075 Goettingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, 37073 Goettingen, Germany; Max Planck Institute for Experimental Medicine, Goettingen, Germany touteir@gwdg.de.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004777:Environment; D020022:Genetic Predisposition to Disease; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism*; D000072756:Protein Conformation, alpha-Helical; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D006639:Histidine; D003300:Copper
keywords: H50Q mutation; copper; inclusions; protein aggregation; α-synuclein