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

Authors

  • Damla Pinar Karpinar,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
    2. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    3. International Max Planck Research School for Molecular Biology, Göttingen, Germany
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    • These authors contributed equally to this work
  • Madhu Babu Gajula Balija,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
    2. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    3. International Max Planck Research School for Molecular Biology, Göttingen, Germany
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    • These authors contributed equally to this work
  • Sebastian Kügler,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Department of Neurology, Medical School, University of Göttingen, Göttingen, Germany
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    • These authors contributed equally to this work
  • Felipe Opazo,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Department for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, Göttingen, Germany
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    • These authors contributed equally to this work
  • Nasrollah Rezaei-Ghaleh,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Nora Wender,

    1. Molecular Neurogenetics Group, European Neuroscience Institute, Göttingen, Germany
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  • Hai-Young Kim,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Grit Taschenberger,

    1. Department of Neurology, Medical School, University of Göttingen, Göttingen, Germany
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  • Björn H Falkenburger,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Department for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, Göttingen, Germany
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  • Henrike Heise,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Ashutosh Kumar,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Dietmar Riedel,

    1. Department for Electron Microscopy, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Lars Fichtner,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, University of Göttingen, Göttingen, Germany
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  • Aaron Voigt,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Department for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, Göttingen, Germany
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  • Gerhard H Braus,

    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, University of Göttingen, Göttingen, Germany
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  • Karin Giller,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Stefan Becker,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Alf Herzig,

    1. Department of Molecular Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Marc Baldus,

    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Herbert Jäckle,

    1. Department of Molecular Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
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  • Stefan Eimer,

    Corresponding author
    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Molecular Neurogenetics Group, European Neuroscience Institute, Göttingen, Germany
    • Corresponding authors: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2220; Fax: +49 551 201 2202; E-mail: mzwecks@gwdg.deDepartment for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2201; E-mail: cigr@nmr.mpibpc.mpg.deDepartment for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany. Tel.: +49 551 39 13540; Fax: +49 551 39 13541; E-mail: jschulz4@gwdg.deMolecular Neurogenetics Group, European Neuroscience Institute, 37077 Göttingen, Germany. Tel.: +49 551 12379; Fax: +49 551 39 10129; E-mail: seimer@gwdg.de

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  • Jörg B Schulz,

    Corresponding author
    1. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    2. Department for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, Göttingen, Germany
    • Corresponding authors: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2220; Fax: +49 551 201 2202; E-mail: mzwecks@gwdg.deDepartment for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2201; E-mail: cigr@nmr.mpibpc.mpg.deDepartment for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany. Tel.: +49 551 39 13540; Fax: +49 551 39 13541; E-mail: jschulz4@gwdg.deMolecular Neurogenetics Group, European Neuroscience Institute, 37077 Göttingen, Germany. Tel.: +49 551 12379; Fax: +49 551 39 10129; E-mail: seimer@gwdg.de

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  • Christian Griesinger,

    Corresponding author
    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
    2. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    • Corresponding authors: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2220; Fax: +49 551 201 2202; E-mail: mzwecks@gwdg.deDepartment for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2201; E-mail: cigr@nmr.mpibpc.mpg.deDepartment for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany. Tel.: +49 551 39 13540; Fax: +49 551 39 13541; E-mail: jschulz4@gwdg.deMolecular Neurogenetics Group, European Neuroscience Institute, 37077 Göttingen, Germany. Tel.: +49 551 12379; Fax: +49 551 39 10129; E-mail: seimer@gwdg.de

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  • Markus Zweckstetter

    Corresponding author
    1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany
    2. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany
    • Corresponding authors: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2220; Fax: +49 551 201 2202; E-mail: mzwecks@gwdg.deDepartment for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37077, Germany. Tel.: +49 551 201 2201; E-mail: cigr@nmr.mpibpc.mpg.deDepartment for Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany. Tel.: +49 551 39 13540; Fax: +49 551 39 13541; E-mail: jschulz4@gwdg.deMolecular Neurogenetics Group, European Neuroscience Institute, 37077 Göttingen, Germany. Tel.: +49 551 12379; Fax: +49 551 39 10129; E-mail: seimer@gwdg.de

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Abstract

The relation of α-synuclein (αS) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated αS species have in neurotoxicity in vivo, we generated αS variants by a structure-based rational design. Biophysical analysis revealed that the αS mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar αS mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between αS aggregates with impaired β-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric αS species and their in vivo function.

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