title: Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models.
abstract: The relation of alpha-synuclein (alphaS) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated alphaS species have in neurotoxicity in vivo, we generated alphaS variants by a structure-based rational design. Biophysical analysis revealed that the alphaS mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar alphaS mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between alphaS aggregates with impaired beta-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric alphaS species and their in vivo function.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany.
authors.forename: Damla Pinar
authors.initials: DP
authors.lastname: Karpinar
authors.forename: Madhu Babu Gajula
authors.initials: MB
authors.lastname: Balija
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Felipe
authors.initials: F
authors.lastname: Opazo
authors.forename: Nasrollah
authors.initials: N
authors.lastname: Rezaei-Ghaleh
authors.forename: Nora
authors.initials: N
authors.lastname: Wender
authors.forename: Hai-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Grit
authors.initials: G
authors.lastname: Taschenberger
authors.forename: Björn H
authors.initials: BH
authors.lastname: Falkenburger
authors.forename: Henrike
authors.initials: H
authors.lastname: Heise
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Dietmar
authors.initials: D
authors.lastname: Riedel
authors.forename: Lars
authors.initials: L
authors.lastname: Fichtner
authors.forename: Aaron
authors.initials: A
authors.lastname: Voigt
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Alf
authors.initials: A
authors.lastname: Herzig
authors.forename: Marc
authors.initials: M
authors.lastname: Baldus
authors.forename: Herbert
authors.initials: H
authors.lastname: Jäckle
authors.forename: Stefan
authors.initials: S
authors.lastname: Eimer
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein