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EMBO J. 2018 Apr 3;37(7). pii: e98049. doi: 10.15252/embj.201798049. Epub 2018 Feb 22.

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

Author information

1
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA swegmann@mgh.harvard.edu bhyman@mgh.harvard.edu.
2
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
3
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
4
Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
5
Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
6
Max-Planck Institute for Molecular Cell Biology & Genetics, Dresden, Germany.
7
Max-Planck Institute for Metabolism Research, Hamburg Outstation c/o DESY, Hamburg, Germany.
8
CAESAR Research Center, Bonn, Germany.
9
Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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

PMID:
29472250
PMCID:
PMC5881631
DOI:
10.15252/embj.201798049
[Indexed for MEDLINE]
Free PMC Article

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