.....To investigate how alpha-Syn oligomers may be linked to aberrant neurite pathology, we modeled different stages of alpha-Syn aggregation in vitro and investigated their interaction with proteins involved in axonal transport. The interaction of wild type alpha-Syn (WTS) and alpha-Syn variants (E57K, A30P, aSyn30-110) with kinesin, tubulin, and the microtubule (MT) associated proteins, MAP2 and Tau, is stronger for multimers than for monomers. WTS seeds, but not alpha-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 alpha-Syn oligomers but not WTS seeds or fibrils (aSyn30-110 multimers). In a human dopaminergic neuronal cell line, mild overexpression of the oligomerizing E57K alpha-Syn variant significantly impaired neurite network morphology without causing profound cell death. In accordance with these findings, MT stability, neuritic kinesin and neuritic kinesin-dependant cargos were significantly reduced by the presence of alpha-Syn oligomers. In summary, different alpha-Syn species act divergently on the axonal transport machinery. These findings provide new insights into alpha-Syn oligomer-driven neuritic pathology as one of the earliest events in synucleinopathies.