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  Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates

Hochmair, J., Exner, C., Franck, M., Dominguez-Baquero, A., Diez, L., Brognaro, H., et al. (2022). Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates. The EMBO Journal, 2022: e108882. doi:10.15252/embj.2021108882.

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EMBO Journal_Hochmair et al_2022.pdf (Publisher version), 6MB
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 Creators:
Hochmair, Janine , Author
Exner, Christian , Author
Franck, Maximilian, Author
Dominguez-Baquero, Alvaro, Author
Diez, Lisa, Author
Brognaro, Hévila, Author
Kraushar, Matthew1, Author              
Mielke, Thorsten2, Author              
Radbruch, Helena , Author
Kaniyappan, Senthil , Author
Falke, Sven, Author
Mandelkow, Eckhard , Author
Betzel, Christian , Author
Wegmann, Susanne, Author
Affiliations:
1High-Resolution Neurogenetics (Matthew Kraushar), Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3374910              
2Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              

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Free keywords: aggregation; FLIM; liquid–liquid phase separation; MAPT; nuclearenvelope
 Abstract: Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate-like density for nuclear-envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

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Language(s): eng - English
 Dates: 2022-02-152022-03-17
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.15252/embj.2021108882
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Title: The EMBO Journal
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 2022 Sequence Number: e108882 Start / End Page: - Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061_1