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  In situ architecture of neuronal alpha-Synuclein inclusions

Trinkaus, V. A., Riera-Tur, I., Martinez Sanchez, A., Bäuerlein, F. J. B., Guo, Q., Arzberger, T., et al. (2021). In situ architecture of neuronal alpha-Synuclein inclusions. Nature Communications, 12(1): 2110. doi:10.1038/s41467-021-22108-0.

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 Creators:
Trinkaus, Victoria A.1, Author              
Riera-Tur, Irene2, Author
Martinez Sanchez, Antonio3, Author              
Bäuerlein, Felix J. B.3, Author              
Guo, Qiang3, Author
Arzberger, Thomas2, Author
Baumeister, Wolfgang3, Author              
Dudanova, Irina2, Author
Hipp, Mark S.1, Author              
Hartl, F. Ulrich1, Author              
Fernandez-Busnadiego, Ruben3, Author              
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2external, ou_persistent22              
3Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: Science & Technology - Other Topics;
 Abstract: The molecular architecture of alpha -Synuclein (alpha -Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. alpha -Syn inclusions were long thought to consist mainly of alpha -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 alpha -Syn inclusions in situ at molecular resolution. We show that inclusions seeded by alpha -Syn aggregates produced recombinantly or purified from patient brain consist of alpha -Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small alpha -Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that alpha -Syn fibrils do not contact membranes directly, and that alpha -Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal alpha -Syn inclusions consist of alpha -Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction. The molecular architecture of alpha -Synuclein (alpha -Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. Here, authors use cryo-electron tomography to image neuronal alpha -Syn inclusions in situ and find that inclusions consist of alpha -Syn fibrils intermixed with cellular organelles without interacting directly.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published online
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 12 (1) Sequence Number: 2110 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723