Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy structure at a resolution of 3.4Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.
- Ricardo Guerrero-Ferreira
- Nicholas M I Taylor
- Henning Stahlberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Sjors HW Scheres, Reviewing Editor, MRC Laboratory of Molecular Biology, United Kingdom
- Received: March 5, 2018
- Accepted: July 1, 2018
- Accepted Manuscript published: July 3, 2018 (version 1)
© 2018, Guerrero-Ferreira et al.
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