Journal
BIOCHEMISTRY
Volume 54, Issue 9, Pages 1831-1840Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.5b00087
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Funding
- National Research Foundation of Korea - MEST [NRF-2013R1A1A2063302]
- Nano Material Technology Development Program of MSIP/NRF [NRF-2014M3A7B6034580]
- National Institutes of Health [R01 GM051290]
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Alzheimers disease (AD) and Parkinsons disease (PD) are caused by beta-amyloid (A beta) and a-synuclein (alpha 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 beta and alpha S coexistence are still elusive. Here, we show that large-sized alpha S oligomers, which are normally difficult to form, are readily generated by A beta(42)-seeding and that these oligomers efficiently hamper neuronal SNARE-mediated vesicle fusion. The direct binding of the A beta-seeded alpha 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 beta(42) oligomers (or aggregates) or the products of alpha S incubated without A beta(42) have no effect on vesicle fusion. These results are confirmed by examining PC12 cell exocytosis. Our results suggest that A beta and alpha S cooperate to escalate the production of toxic oligomers, whose main toxicity is the inhibition of vesicle fusion and consequently prompts synaptic dysfunction.
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