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Tau protein liquid-liquid phase separation can initiate tau aggregation.
Journal article

Tau protein liquid-liquid phase separation can initiate tau aggregation.

  • Wegmann S Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA swegmann@mgh.harvard.edu bhyman@mgh.harvard.edu.
  • Eftekharzadeh B Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Tepper K German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • Zoltowska KM Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Bennett RE Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Dujardin S Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Laskowski PR Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • MacKenzie D Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Kamath T Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Commins C Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Vanderburg C Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Roe AD Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Fan Z Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Molliex AM Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Hernandez-Vega A Max-Planck Institute for Molecular Cell Biology & Genetics, Dresden, Germany.
  • Muller D Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • Hyman AA Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • Mandelkow E German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • Taylor JP Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Hyman BT Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA swegmann@mgh.harvard.edu bhyman@mgh.harvard.edu.
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  • 2018-02-24
Published in:
  • The EMBO journal. - 2018
Alzheimer's disease
aggregation
liquid–liquid phase separation
phosphorylation
tau
Aged, 80 and over
Alzheimer Disease
Amino Acid Sequence
Amyotrophic Lateral Sclerosis
Animals
Benzothiazoles
Biophysical Phenomena
Brain
Cloning, Molecular
DNA-Binding Proteins
Escherichia coli
Female
HEK293 Cells
Heterogeneous Nuclear Ribonucleoprotein A1
Humans
Liquid-Liquid Extraction
Mice
Mice, Transgenic
Molecular Weight
Neuroblastoma
Neurodegenerative Diseases
Neurofibrillary Tangles
Neurons
Phosphorylation
Protein Aggregation, Pathological
Recombinant Proteins
Sequence Analysis, Protein
Sf9 Cells
tau Proteins
English The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain. Droplet-like tau can also be observed in neurons and other cells. We found that tau droplets become gel-like in minutes, and over days start to spontaneously form thioflavin-S-positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/24113
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