title: β-Amyloid and α-synuclein cooperate to block SNARE-dependent vesicle fusion.
abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are caused by β-amyloid (Aβ) and α-synuclein (αS), 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 Aβ and αS coexistence are still elusive. Here, we show that large-sized αS oligomers, which are normally difficult to form, are readily generated by Aβ42-seeding and that these oligomers efficiently hamper neuronal SNARE-mediated vesicle fusion. The direct binding of the Aβ-seeded αS oligomers to the N-terminal domain of synaptobrevin-2, a vesicular SNARE protein, is responsible for the inhibition of fusion. In contrast, large-sized Aβ42 oligomers (or aggregates) or the products of αS incubated without Aβ42 have no effect on vesicle fusion. These results are confirmed by examining PC12 cell exocytosis. Our results suggest that Aβ and αS cooperate to escalate the production of toxic oligomers, whose main toxicity is the inhibition of vesicle fusion and consequently prompts synaptic dysfunction.
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering and ‡Department of Physics, Pohang University of Science and Technology , Pohang 790-784, Korea.
authors.forename: Bong-Kyu
authors.initials: BK
authors.lastname: Choi
authors.forename: Jae-Yeol
authors.initials: JY
authors.lastname: Kim
authors.forename: Moon-Yong
authors.initials: MY
authors.lastname: Cha
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: Yeon-Kyun
authors.initials: YK
authors.lastname: Shin
authors.forename: Nam Ki
authors.initials: NK
authors.lastname: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D022162:Cytoplasmic Vesicles / Q000502:physiology*; D005089:Exocytosis / Q000235:genetics; D006801:Humans; D008561:Membrane Fusion / Q000235:genetics; D016716:PC12 Cells; D011485:Protein Binding / Q000235:genetics; D055503:Protein Multimerization / Q000502:physiology; D051381:Rats; D050600:SNARE Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D050600:SNARE Proteins; D051844:alpha-Synuclein