Significanceα-Synuclein (α-Syn) aggregation underlies neurodegeneration in synucleinopathies. However, the nature of α-Syn aggregates and their toxic mechanisms in human pathology remains elusive. Here, we delineate a role of α-Syn oligomeric aggregates for axonal integrity in human neuronal models of synucleinopathies. α-Syn oligomers disrupt anterograde axonal transport of mitochondria by causing subcellular changes in transport-regulating proteins and energy deficits. An increase of α-Syn oligomers in human neurons finally results in synaptic degeneration. Together, our data provide mechanistic insights of α-Syn oligomeric toxicity in human neurons. Taking into account that α-Syn oligomers and axonal dysfunction are characteristic for early neurodegeneration in synucleinopathies, our data might deliver targets for therapeutic interference with early disease pathology.

Background: ␣-Synuclein aggregates cause early neurite pathology by as yet unknown mechanisms. Results: ␣-Synuclein oligomers and seeds decrease microtubule stability, kinesin-microtubule interaction, cellular cargo distribution, and neurite network morphology. Conclusion: Various ␣-synuclein species interact differently with proteins of axonal transport. Significance: The impairment of the microtubule-kinesin function by ␣-synuclein oligomers drives early neurite pathology.