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In situ architecture of neuronal alpha-Synuclein inclusions

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Trinkaus,  Victoria A.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Martinez Sanchez,  Antonio
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Bäuerlein,  Felix J. B.
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

Guo,  Qiang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Baumeister,  Wolfgang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Hipp,  Mark S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Hartl,  F. Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Fernandez-Busnadiego,  Ruben
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0008-9224-A
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.