Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope

Janine Hochmair, Christian Exner, Maximilian Franck, Alvaro Dominguez-Baquero, Lisa Diez, Hévila Brognaro, Matthew Kraushar, Thorsten Mielke, Helena Radbruch, View ORCID ProfileSenthil Kaniyappan, Sven Falke, Eckhard Mandelkow, Christian Betzel, View ORCID ProfileSusanne Wegmann
doi: https://doi.org/10.1101/2022.01.24.477544
Janine Hochmair
1German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Exner
2Institute for Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, 22603 Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maximilian Franck
1German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alvaro Dominguez-Baquero
1German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Diez
1German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hévila Brognaro
2Institute for Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, 22603 Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew Kraushar
3Max Planck Institute for Molecular Genetics (MOLGEN), 14195 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thorsten Mielke
3Max Planck Institute for Molecular Genetics (MOLGEN), 14195 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Helena Radbruch
4Institute for Neuropathology, Charité Berlin, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Senthil Kaniyappan
5German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
6Department of Neurodegenerative Diseases and Geriatric Psychiatry, Univ. Bonn (Germany)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Senthil Kaniyappan
Sven Falke
2Institute for Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, 22603 Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eckhard Mandelkow
5German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
6Department of Neurodegenerative Diseases and Geriatric Psychiatry, Univ. Bonn (Germany)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Betzel
2Institute for Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, 22603 Hamburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Wegmann
1German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Susanne Wegmann
  • For correspondence: susanne.wegmann@dzne.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

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, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small 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.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations and Definitions

    AD
    Alzheimer’s disease
    CFP
    cyan fluorescent protein
    DLS
    dynamic light scattering
    FTD
    frontotemporal dementia
    LLPS
    liquid-liquid phase separation
    MTs
    microtubules
    R0
    radius of hydration (Stokes radius)
    YFP
    yellow fluorescent protein
    FRAP
    fluorescence recovery after photobleaching
    FLIM
    fluorescence lifetime imaging microscopy
    FRET-FLIM
    Foerster Resonance energy transfer measured by FLIM of the donor
    CYT
    cytosolic Tau inclusions
    NUC
    intranuclear Tau accumulations
    NE
    Tau accumulations at the nuclear envelope
    hepAGG
    Tau aggregated in the presence of heparin at a 4:1 (Tau:heparin) ratio
    mesoscopic clusters
    R0 ∼100-200 nm
    microscopic condensates
    R0 ∼1000 nm
    monomeric/clusters/condensates
    refers to degree of Tau assembling
    Tau coacervation
    LLPS driven by interaction of Tau with polyanions in the presence of PEG
    Tau condensation
    term for all LLPS processes
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
    Back to top
    PreviousNext
    Posted January 25, 2022.
    Download PDF
    Email

    Thank you for your interest in spreading the word about bioRxiv.

    NOTE: Your email address is requested solely to identify you as the sender of this article.

    Enter multiple addresses on separate lines or separate them with commas.
    Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope
    (Your Name) has forwarded a page to you from bioRxiv
    (Your Name) thought you would like to see this page from the bioRxiv website.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Share
    Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope
    Janine Hochmair, Christian Exner, Maximilian Franck, Alvaro Dominguez-Baquero, Lisa Diez, Hévila Brognaro, Matthew Kraushar, Thorsten Mielke, Helena Radbruch, Senthil Kaniyappan, Sven Falke, Eckhard Mandelkow, Christian Betzel, Susanne Wegmann
    bioRxiv 2022.01.24.477544; doi: https://doi.org/10.1101/2022.01.24.477544
    Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
    Citation Tools
    Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope
    Janine Hochmair, Christian Exner, Maximilian Franck, Alvaro Dominguez-Baquero, Lisa Diez, Hévila Brognaro, Matthew Kraushar, Thorsten Mielke, Helena Radbruch, Senthil Kaniyappan, Sven Falke, Eckhard Mandelkow, Christian Betzel, Susanne Wegmann
    bioRxiv 2022.01.24.477544; doi: https://doi.org/10.1101/2022.01.24.477544

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Subject Area

    • Molecular Biology
    Subject Areas
    All Articles
    • Animal Behavior and Cognition (3505)
    • Biochemistry (7346)
    • Bioengineering (5323)
    • Bioinformatics (20263)
    • Biophysics (10016)
    • Cancer Biology (7743)
    • Cell Biology (11300)
    • Clinical Trials (138)
    • Developmental Biology (6437)
    • Ecology (9951)
    • Epidemiology (2065)
    • Evolutionary Biology (13322)
    • Genetics (9361)
    • Genomics (12583)
    • Immunology (7701)
    • Microbiology (19021)
    • Molecular Biology (7441)
    • Neuroscience (41036)
    • Paleontology (300)
    • Pathology (1229)
    • Pharmacology and Toxicology (2137)
    • Physiology (3160)
    • Plant Biology (6860)
    • Scientific Communication and Education (1272)
    • Synthetic Biology (1896)
    • Systems Biology (5311)
    • Zoology (1089)