title: Copper(II) and the pathological H50Q α-synuclein mutant: Environment meets genetics.
abstract: Copper is one of the metals described to bind the Parkinson disease-related protein α-synuclein (aSyn), and to promote its aggregation. Although histidine at position 50 in the aSyn sequence is one of the most studied copper-anchoring sites, its precise role in copper binding and aSyn aggregation is still unclear. Previous studies suggested that this residue does not significantly affect copper-mediated aSyn aggregation. However, our findings showed that the aggregation of the pathological H50Q aSyn mutant is enhanced by copper hints otherwise. Despite the inexistence of a model for aSyn H50Q-copper complexation, we discuss possible mechanisms by which this metal contributes to the misfolding and self-assembly of this particular aSyn mutant. Considering the genetic association of the H50Q mutation with familial forms of Parkinson disease, and the fact that copper homeostasis is deregulated in this disorder, understanding the interplay between both factors will shed light into the molecular and cellular mechanisms triggering the development and spreading of the aSyn pathology.
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen , Göttingen , Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Villar-Piqué
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Jülich, Germany; Department of Oncology, Hematology, and Stem Cell Transplantation, Medical School, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany; Simulation Laboratory Biology - Jülich Supercomputing Centre (JSC), Jülich, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona , Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9 , 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, Santa Fe, 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, Rosario, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Centre Göttingen, Göttingen, Germany; Max Planck Institute for Experimental Medicine, Göttingen, Germany.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
keywords: H50Q mutation; Parkinson disease; amyloid; copper; protein aggregation; α-synuclein