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Title: Structure of the toxic core of α-synuclein from invisible crystals

We report that the protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. Finally, the NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
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  1. Univ. of California, Los Angeles, CA (United States). Howard Hughes Medical Institute/UCLA-DOE Institute
  2. Howard Hughes Medical Institute, Ashburn, VA (United States)
  3. Univ. of California, Los Angeles, CA (United States). NPI-Semel Institute
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC02-06CH11357; AC02-05CH11231; FC02-02ER63421; NIH-AG016570
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 525; Journal Issue: 7570; Journal ID: ISSN 0028-0836
Nature Publishing Group
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
National Institutes of Health (NIH)
Country of Publication:
United States
Parkinson's disease; Lewy bodies; α-synuclein