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PMID: 29472250 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 37 ·No. 7 ·2018-00-03

Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C, Vanderburg C, Roe AD, Fan Z, Molliex AM, Hernandez-Vega A, Muller D, Hyman AA, Mandelkow E, Taylor JP, Hyman BT

Abstract

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.

Keywords
Alzheimer's disease aggregation liquid–liquid phase separation phosphorylation tau
MeSH Terms
Aged, 80 and over Alzheimer Disease/metabolism Amino Acid Sequence Amyotrophic Lateral Sclerosis/metabolism Animals Benzothiazoles/metabolism Biophysical Phenomena Brain/metabolism Cloning, Molecular DNA-Binding Proteins/metabolism Escherichia coli/genetics Female HEK293 Cells Heterogeneous Nuclear Ribonucleoprotein A1/metabolism Humans Liquid-Liquid Extraction Mice Mice, Transgenic Molecular Weight Neuroblastoma/metabolism Neurodegenerative Diseases/metabolism Neurofibrillary Tangles/metabolism Neurons/metabolism Phosphorylation Protein Aggregation, Pathological/metabolism Recombinant Proteins/genetics,metabolism Sequence Analysis, Protein Sf9 Cells tau Proteins/chemistry,isolation & purification,metabolism
Chemicals
Benzothiazoles DNA-Binding Proteins Heterogeneous Nuclear Ribonucleoprotein A1 Recombinant Proteins TARDBP protein, human hnRNPA1 protein, human tau Proteins thioflavin T
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Wegmann Susanne ORCID
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA swegmann@mgh.harvard.edu bhyman@mgh.harvard.edu.
Eftekharzadeh Bahareh
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Tepper Katharina
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Zoltowska Katarzyna M
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Bennett Rachel E
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Dujardin Simon
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Laskowski Pawel R ORCID
Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
MacKenzie Danny
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Kamath Tarun
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Commins Caitlin
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Vanderburg Charles
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Roe Allyson D
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Fan Zhanyun
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Molliex Amandine M
Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Hernandez-Vega Amayra
Max-Planck Institute for Molecular Cell Biology & Genetics, Dresden, Germany.
Muller Daniel ORCID
Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Hyman Anthony A
Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Mandelkow Eckhard
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. | Max-Planck Institute for Metabolism Research, Hamburg Outstation c/o DESY, Hamburg, Germany. | CAESAR Research Center, Bonn, Germany.
Taylor J Paul
Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. | Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Hyman Bradley T ORCID
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA swegmann@mgh.harvard.edu bhyman@mgh.harvard.edu.
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.15252/embj.201798049
Email
swegmann@mgh.harvard.edu
bhyman@mgh.harvard.edu
Published
2018-00-03
Epub
2018-00-22
Language
English
Region
England
NLM ID
8208664
PMCID
PMC5881631
Subset
IM
Grants
NIA NIH HHS · P50 AG005134 · United States
NINDS NIH HHS · R35 NS097974 · United States
External Links
PubMed source DOI: 10.15252/embj.201798049 PMC Full Text View journal details
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