?-Amyloid and ?-synuclein cooperate to block SNARE-dependent vesicle fusion.

ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD) are caused by ?-amyloid (A?) and ?-synuclein (?S), respectively. Ample evidence suggests that these two pathogenic proteins are closely linked and have a synergistic effect on eliciting neurodegenerative disorders. However, the pathophysiological consequences of A? and ?S coexistence are still elusive. Here, we show that large-sized ?S oligomers, which are normally difficult to form, are readily generated by A?42-seeding and that these oligomers efficiently hamper neuronal SNARE-mediated vesicle fusion. The direct binding of the A?-seeded ?S oligomers to the N-terminal domain of synaptobrevin-2, a vesicular SNARE protein, is responsible for the inhibition of fusion. In contrast, large-sized A?42 oligomers (or aggregates) or the products of ?S incubated without A?42 have no effect on vesicle fusion. These results are confirmed by examining PC12 cell exocytosis. Our results suggest that A? and ?S cooperate to escalate the production of toxic oligomers, whose main toxicity is the inhibition of vesicle fusion and consequently prompts synaptic dysfunction.

SUBMITTER: Choi BK 

PROVIDER: S-EPMC4414064 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature