Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 8, Pages 3246-3251Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1013225108
Keywords
alpha-synuclein; amyloid; structral nucleus; solution structure
Categories
Funding
- Danish Ministry of Science, Technology, and Innovation
- Danish National Research Foundation (inSPIN)
- Danish Council for Independent Research in Medical Sciences
- DANSCATT
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One of the major hallmarks of Parkinson disease is aggregation of the protein alpha-synuclein (alpha SN). Aggregate cytotoxicity has been linked to an oligomeric species formed at early stages in the aggregation process. Here we follow the fibrillation process of alpha SN in solution over time using small angle X-ray scattering and resolve four major coexisting species in the fibrillation process, namely monomer, dimer, fibril and an oligomer. By ab initio modeling to fit the data, we obtain a low-resolution structure of a symmetrical and slender alpha SN fibril in solution, consisting of a repeating unit with a maximal distance of 900 angstrom and a diameter of similar to 180 angstrom. The same approach shows the oligomer to be shaped like a wreath, with a central channel and with dimensions corresponding to the width of the fibril. The structure, accumulation and decay of this oligomer is consistent with an on-pathway role for the oligomer in the fibrillation process. We propose an oligomer-driven alpha SN fibril formation mechanism, where the fibril is built from the oligomers. The wreath-shaped structure of the oligomer highlights its potential cytotoxicity by simple membrane permeabilization. This is confirmed by the ability of the purified oligomer to disrupt liposomes. Our results provide the first structural description in solution of a potentially cytotoxic oligomer, which accumulates during the fibrillation of alpha SN.
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