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

Abstract

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.

Authors:
 [1];  [1];  [1];  [1];  [2];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [5];  [5];  [4];  [2] more »;  [1] « less
  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:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1222837
Alternate Identifier(s):
OSTI ID: 1513790
Grant/Contract Number:  
AC02-06CH11357; AC02-05CH11231; FC02-02ER63421; NIH-AG016570
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 525; Journal Issue: 7570; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
Parkinson's disease; Lewy bodies; α-synuclein

Citation Formats

Rodriguez, Jose A., Ivanova, Magdalena I., Sawaya, Michael R., Cascio, Duilio, Reyes, Francis E., Shi, Dan, Sangwan, Smriti, Guenther, Elizabeth L., Johnson, Lisa M., Zhang, Meng, Jiang, Lin, Arbing, Mark A., Nannenga, Brent L., Hattne, Johan, Whitelegge, Julian, Brewster, Aaron S., Messerschmidt, Marc, Boutet, Sébastien, Sauter, Nicholas K., Gonen, Tamir, and Eisenberg, David S. Structure of the toxic core of α-synuclein from invisible crystals. United States: N. p., 2015. Web. doi:10.1038/nature15368.
Rodriguez, Jose A., Ivanova, Magdalena I., Sawaya, Michael R., Cascio, Duilio, Reyes, Francis E., Shi, Dan, Sangwan, Smriti, Guenther, Elizabeth L., Johnson, Lisa M., Zhang, Meng, Jiang, Lin, Arbing, Mark A., Nannenga, Brent L., Hattne, Johan, Whitelegge, Julian, Brewster, Aaron S., Messerschmidt, Marc, Boutet, Sébastien, Sauter, Nicholas K., Gonen, Tamir, & Eisenberg, David S. Structure of the toxic core of α-synuclein from invisible crystals. United States. doi:10.1038/nature15368.
Rodriguez, Jose A., Ivanova, Magdalena I., Sawaya, Michael R., Cascio, Duilio, Reyes, Francis E., Shi, Dan, Sangwan, Smriti, Guenther, Elizabeth L., Johnson, Lisa M., Zhang, Meng, Jiang, Lin, Arbing, Mark A., Nannenga, Brent L., Hattne, Johan, Whitelegge, Julian, Brewster, Aaron S., Messerschmidt, Marc, Boutet, Sébastien, Sauter, Nicholas K., Gonen, Tamir, and Eisenberg, David S. Wed . "Structure of the toxic core of α-synuclein from invisible crystals". United States. doi:10.1038/nature15368. https://www.osti.gov/servlets/purl/1222837.
@article{osti_1222837,
title = {Structure of the toxic core of α-synuclein from invisible crystals},
author = {Rodriguez, Jose A. and Ivanova, Magdalena I. and Sawaya, Michael R. and Cascio, Duilio and Reyes, Francis E. and Shi, Dan and Sangwan, Smriti and Guenther, Elizabeth L. and Johnson, Lisa M. and Zhang, Meng and Jiang, Lin and Arbing, Mark A. and Nannenga, Brent L. and Hattne, Johan and Whitelegge, Julian and Brewster, Aaron S. and Messerschmidt, Marc and Boutet, Sébastien and Sauter, Nicholas K. and Gonen, Tamir and Eisenberg, David S.},
abstractNote = {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.},
doi = {10.1038/nature15368},
journal = {Nature (London)},
number = 7570,
volume = 525,
place = {United States},
year = {2015},
month = {9}
}

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    Works referencing / citing this record:

    Micro-Electron Diffraction data from alpha-synuclein, source of 4RIL structure
    dataset, November 2015

    • Rodriguez, Jose A.; Reyes, Francis E.; Gonen, Tamir
    • SBGrid Data Bank
    • DOI: 10.15785/sbgrid/193

    Micro-Electron Diffraction data from alpha-synuclein, source of 4RIL structure
    dataset, March 2016

    • Rodriguez, Jose A.; Reyes, Francis E.; Gonen, Tamir
    • SBGrid Data Bank
    • DOI: 10.15785/sbgrid/223

    The new mutation, E46K, of α-synuclein causes parkinson and Lewy body dementia: New α-Synuclein Gene Mutation
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    • Zarranz, Juan J.; Alegre, Javier; Gómez-Esteban, Juan C.
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    • Journal of Molecular Biology, Vol. 411, Issue 4
    • DOI: 10.1016/j.jmb.2011.06.026

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    journal, June 2010

    • Rao, Jampani Nageswara; Jao, Christine C.; Hegde, Balachandra G.
    • Journal of the American Chemical Society, Vol. 132, Issue 25
    • DOI: 10.1021/ja100646t

    Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease
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    • Conway, Kelly A.; Harper, James D.; Lansbury, Peter T.
    • Nature Medicine, Vol. 4, Issue 11
    • DOI: 10.1038/3311

    α-Synuclein in Lewy bodies
    journal, August 1997

    • Spillantini, Maria Grazia; Schmidt, Marie Luise; Lee, Virginia M. -Y.
    • Nature, Vol. 388, Issue 6645
    • DOI: 10.1038/42166

    Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models
    journal, September 2009

    • Karpinar, Damla Pinar; Balija, Madhu Babu Gajula; Kügler, Sebastian
    • The EMBO Journal, Vol. 28, Issue 20
    • DOI: 10.1038/emboj.2009.257

    Structure of the cross-β spine of amyloid-like fibrils
    journal, June 2005

    • Nelson, Rebecca; Sawaya, Michael R.; Balbirnie, Melinda
    • Nature, Vol. 435, Issue 7043
    • DOI: 10.1038/nature03680

    Atomic structures of amyloid cross-β spines reveal varied steric zippers
    journal, April 2007

    • Sawaya, Michael R.; Sambashivan, Shilpa; Nelson, Rebecca
    • Nature, Vol. 447, Issue 7143
    • DOI: 10.1038/nature05695

    Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation
    journal, June 2011

    • Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.
    • Nature, Vol. 475, Issue 7354
    • DOI: 10.1038/nature10154

    Structural and functional characterization of two alpha-synuclein strains
    journal, October 2013

    • Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma
    • Nature Communications, Vol. 4, Issue 1
    • DOI: 10.1038/ncomms3575

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    Accurate macromolecular structures using minimal measurements from X-ray free-electron lasers
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    • Hattne, Johan; Echols, Nathaniel; Tran, Rosalie
    • Nature Methods, Vol. 11, Issue 5
    • DOI: 10.1038/nmeth.2887

    High-resolution structure determination by continuous-rotation data collection in MicroED
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    • Goedert, Michel; Spillantini, Maria Grazia; Del Tredici, Kelly
    • Nature Reviews Neurology, Vol. 9, Issue 1
    • DOI: 10.1038/nrneurol.2012.242

    Identification of the region of non-Aβ component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity: Bioactive region of NAC
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    Injector for scattering measurements on fully solvated biospecies
    journal, March 2012

    • Weierstall, U.; Spence, J. C. H.; Doak, R. B.
    • Review of Scientific Instruments, Vol. 83, Issue 3
    • DOI: 10.1063/1.3693040

     -Synuclein structures from fluorescence energy-transfer kinetics: Implications for the role of the protein in Parkinson's disease
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    • Lee, J. C.; Langen, R.; Hummel, P. A.
    • Proceedings of the National Academy of Sciences, Vol. 101, Issue 47
    • DOI: 10.1073/pnas.0407307101

    The fold of  -synuclein fibrils
    journal, June 2008

    • Vilar, M.; Chou, H. -T.; Luhrs, T.
    • Proceedings of the National Academy of Sciences, Vol. 105, Issue 25
    • DOI: 10.1073/pnas.0712179105

    Identifying the amylome, proteins capable of forming amyloid-like fibrils
    journal, February 2010

    • Goldschmidt, Lukasz; Teng, Poh K.; Riek, Roland
    • Proceedings of the National Academy of Sciences, Vol. 107, Issue 8
    • DOI: 10.1073/pnas.0915166107

    In vivo demonstration that  -synuclein oligomers are toxic
    journal, February 2011

    • Winner, B.; Jappelli, R.; Maji, S. K.
    • Proceedings of the National Academy of Sciences, Vol. 108, Issue 10
    • DOI: 10.1073/pnas.1100976108

    Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation
    journal, April 2015

    • Chen, Serene W.; Drakulic, Srdja; Deas, Emma
    • Proceedings of the National Academy of Sciences, Vol. 112, Issue 16
    • DOI: 10.1073/pnas.1421204112

    Electron crystallography of ultrathin 3D protein crystals: Atomic model with charges
    journal, February 2015

    • Yonekura, Koji; Kato, Kazuyuki; Ogasawara, Mitsuo
    • Proceedings of the National Academy of Sciences, Vol. 112, Issue 11
    • DOI: 10.1073/pnas.1500724112

    Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease
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    • Uéda, K.; Fukushima, H.; Masliah, E.
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    • Fabiola, Felcy; Bertram, Richard; Korostelev, Andrei
    • Protein Science, Vol. 11, Issue 6
    • DOI: 10.1110/ps.4890102

    Functional protein kinase arrays reveal inhibition of p-21-activated kinase 4 by α-synuclein oligomers
    journal, December 2007


     -Synuclein Locus Triplication Causes Parkinson's Disease
    journal, October 2003


    Mutation in the -Synuclein Gene Identified in Families with Parkinson's Disease
    journal, June 1997


    Hydrogen positions in single nanocrystals revealed by electron diffraction
    journal, January 2017


    α-Synuclein: Membrane Interactions and Toxicity in Parkinson's Disease
    journal, November 2010


    Targeted Amino-Terminal Acetylation of Recombinant Proteins in E. coli
    journal, December 2010


    Impairment of Mitochondria in Adult Mouse Brain Overexpressing Predominantly Full-Length, N-Terminally Acetylated Human α-Synuclein
    journal, May 2013


    Lipids as Trans-Acting Effectors for α-Synuclein in the Pathogenesis of Parkinson’s Disease
    journal, July 2019