title: Mutant protein A30P α-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics.
abstract: α-Synuclein (AS) is associated with both sporadic and familial forms of Parkinson disease (PD). In sporadic disease, wild-type AS fibrillates and accumulates as Lewy bodies within dopaminergic neurons of the substantia nigra. The accumulation of misfolded AS is associated with the death of these neurons, which underlies many of the clinical features of PD. In addition, a rare missense mutation in AS, A30P, is associated with highly penetrant, autosomal dominant PD, although the pathogenic mechanism is unclear. A30P AS fibrillates more slowly than the wild-type (WT) protein in vitro and has been reported to preferentially adopt a soluble, protofibrillar conformation. This has led to speculation that A30P forms aggregates that are distinct in structure compared with wild-type AS. Here, we perform a detailed comparison of the chemical shifts and secondary structures of these fibrillar species, based upon our recent characterization of full-length WT fibrils. We have assigned A30P AS fibril chemical shifts de novo and used them to determine its secondary structure empirically. Our results illustrate that although A30P forms fibrils more slowly than WT in vitro, the chemical shifts and secondary structure of the resultant fibrils are in high agreement, demonstrating a conserved β-sheet core.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Luisel R
authors.initials: LR
authors.lastname: Lemkau
authors.forename: Gemma
authors.initials: G
authors.lastname: Comellas
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Kloepper
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Woods
authors.forename: Julia M
authors.initials: JM
authors.lastname: George
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
mesh_terms: D006801:Humans; D007700:Kinetics; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D051844:alpha-Synuclein