?-Synuclein oligomers impair neuronal microtubule-kinesin interplay.

ABSTRACT: Early ?-synuclein (?-Syn)-induced alterations are neurite pathologies resulting in Lewy neurites. ?-Syn oligomers are a toxic species in synucleinopathies and are suspected to cause neuritic pathology. To investigate how ?-Syn oligomers may be linked to aberrant neurite pathology, we modeled different stages of ?-Syn aggregation in vitro and investigated the interplay of ?-Syn aggregates with proteins involved in axonal transport. The interaction of wild type ?-Syn (WTS) and ?-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 ?-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 ?-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 ?-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 ?-Syn oligomers. In summary, different ?-Syn species act divergently on the axonal transport machinery. These findings provide new insights into ?-Syn oligomer-driven neuritic pathology as one of the earliest events in synucleinopathies.

SUBMITTER: Prots I 

PROVIDER: S-EPMC3724632 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature