title: α-Synuclein oligomers impair neuronal microtubule-kinesin interplay.
abstract: Early α-synuclein (α-Syn)-induced alterations are neurite pathologies resulting in Lewy neurites. α-Syn oligomers are a toxic species in synucleinopathies and are suspected to cause neuritic pathology. To investigate how α-Syn oligomers may be linked to aberrant neurite pathology, we modeled different stages of α-Syn aggregation in vitro and investigated the interplay of α-Syn aggregates with proteins involved in axonal transport. The interaction of wild type α-Syn (WTS) and α-Syn variants (E57K, A30P, and aSyn(30-110)) with kinesin, tubulin, and the microtubule (MT)-associated proteins, MAP2 and Tau, is stronger for multimers than for monomers. WTS seeds but not α-Syn oligomers significantly and dose-dependently reduced Tau-promoted MT assembly in vitro. In contrast, MT gliding velocity across kinesin-coated surfaces was significantly decreased in the presence of α-Syn oligomers but not WTS seeds or fibrils (aSyn(30-110) multimers). In a human dopaminergic neuronal cell line, mild overexpression of the oligomerizing E57K α-Syn variant significantly impaired neurite network morphology without causing profound cell death. In accordance with these findings, MT stability, neuritic kinesin, and neuritic kinesin-dependent cargoes were significantly reduced by the presence of α-Syn oligomers. In summary, different α-Syn species act divergently on the axonal transport machinery. These findings provide new insights into α-Syn oligomer-driven neuritic pathology as one of the earliest events in synucleinopathies.
authors.affiliation: Junior Research Group III, Nikolaus Fiebiger Centre for Molecular Medicine, Universitaetsklinikum Erlangen, Glueckstrasse 6, 91054 Erlangen, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
authors.forename: Vanesa
authors.initials: V
authors.lastname: Veber
authors.forename: Stefanie
authors.initials: S
authors.lastname: Brey
authors.forename: Silvia
authors.initials: S
authors.lastname: Campioni
authors.forename: Katrin
authors.initials: K
authors.lastname: Buder
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Böhm
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D014404:Tubulin / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C500506:KIF5A protein, human; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D051844:alpha-Synuclein; D016875:tau Proteins; D016547:Kinesins
keywords: Kinesin; Microtubules; Neurite; Neurodegeneration; Oligomers; Transport; alpha-Synuclein