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In situ architecture of neuronal α-Synuclein inclusions

Author

Listed:
  • Victoria A. Trinkaus

    (Max Planck Institute of Biochemistry
    Graduate School of Quantitative Biosciences Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Irene Riera-Tur

    (Max Planck Institute of Neurobiology
    Max Planck Institute of Neurobiology)

  • Antonio Martínez-Sánchez

    (Max Planck Institute of Biochemistry
    University Medical Center Göttingen
    University of Göttingen)

  • Felix J. B. Bäuerlein

    (Max Planck Institute of Biochemistry
    University Medical Center Göttingen
    University of Göttingen)

  • Qiang Guo

    (Max Planck Institute of Biochemistry
    Peking University
    Peking University
    Peking University)

  • Thomas Arzberger

    (Munich Cluster for Systems Neurology (SyNergy)
    Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich
    University Hospital, Ludwig-Maximilians-University Munich)

  • Wolfgang Baumeister

    (Max Planck Institute of Biochemistry)

  • Irina Dudanova

    (Max Planck Institute of Neurobiology
    Max Planck Institute of Neurobiology)

  • Mark S. Hipp

    (Max Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy)
    University Medical Center Groningen, University of Groningen
    Carl von Ossietzky University Oldenburg)

  • F. Ulrich Hartl

    (Max Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy)
    Chevy Chase)

  • Rubén Fernández-Busnadiego

    (Max Planck Institute of Biochemistry
    University Medical Center Göttingen
    University of Göttingen
    Chevy Chase)

Abstract

The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn fibrils, but recent reports pointed to intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) to image neuronal α-Syn inclusions in situ at molecular resolution. We show that inclusions seeded by α-Syn aggregates produced recombinantly or purified from patient brain consist of α-Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that α-Syn fibrils do not contact membranes directly, and that α-Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal α-Syn inclusions consist of α-Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction.

Suggested Citation

  • Victoria A. Trinkaus & Irene Riera-Tur & Antonio Martínez-Sánchez & Felix J. B. Bäuerlein & Qiang Guo & Thomas Arzberger & Wolfgang Baumeister & Irina Dudanova & Mark S. Hipp & F. Ulrich Hartl & Rubén, 2021. "In situ architecture of neuronal α-Synuclein inclusions," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22108-0
    DOI: 10.1038/s41467-021-22108-0
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    Cited by:

    1. Jinhua Dou & Chang Liu & Ruoyu Xiong & Hongguang Zhou & Guohua Lu & Liping Jia, 2022. "Empathy and Post-Traumatic Growth among Chinese Community Workers during the COVID-19 Pandemic: Roles of Self-Disclosure and Social Support," IJERPH, MDPI, vol. 19(23), pages 1-12, November.

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