title: Formation of covalent di-tyrosine dimers in recombinant α-synuclein.
abstract: Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: van Maarschalkerweerd
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: M N
authors.initials: MN
authors.lastname: Pedersen
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Peterson
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: Department of Pharmacy; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: Ttt
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Skamris
authors.affiliation: Department of Pharmacy; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Rand
authors.affiliation: Dipartimento di Fisica e Chimica; Universitá di Palermo ; Palermo, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Vetri
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: A E
authors.initials: AE
authors.lastname: Langkilde
authors.affiliation: Department of Drug Design and Pharmacology; University of Copenhagen ; Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Vestergaard
keywords: EOM; Parkinson's disease; SAXS; amyloids; di-tyrosine dimers; α-synuclein