Tau protein liquid–liquid phase separation can initiate tau aggregation

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...

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Published in:	The EMBO journal Vol. 37; no. 7
Main Authors:	Wegmann, Susanne, Eftekharzadeh, Bahareh, Tepper, Katharina, Zoltowska, Katarzyna M, Bennett, Rachel E, Dujardin, Simon, Laskowski, Pawel R, MacKenzie, Danny, Kamath, Tarun, Commins, Caitlin, Vanderburg, Charles, Roe, Allyson D, Fan, Zhanyun, Molliex, Amandine M, Hernandez‐Vega, Amayra, Muller, Daniel, Hyman, Anthony A, Mandelkow, Eckhard, Taylor, J Paul, Hyman, Bradley T
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03.04.2018 Springer Nature B.V John Wiley and Sons Inc
Subjects:	Aged, 80 and over Agglomeration Aggregates aggregation Alzheimer Disease - metabolism Alzheimer's disease Amino Acid Sequence Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - metabolism Animals Benzothiazoles - metabolism Biophysical Phenomena Brain Brain - metabolism Cloning, Molecular Dementia disorders DNA-Binding Proteins - metabolism Droplets EMBO29 EMBO32 Escherichia coli - genetics Female Forming Frontotemporal dementia HEK293 Cells Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism Humans Liquid-Liquid Extraction liquid–liquid phase separation Mice Mice, Transgenic Molecular Weight Mutation Neuroblastoma - metabolism Neurodegenerative diseases Neurodegenerative Diseases - metabolism Neurofibrillary tangles Neurofibrillary Tangles - metabolism Neurological diseases Neurons Neurons - metabolism Phase separation Phosphorylation Protein Aggregation, Pathological - metabolism Proteins Recombinant Proteins - genetics Recombinant Proteins - metabolism Seeds Sequence Analysis, Protein Sf9 Cells tau Tau protein tau Proteins - chemistry tau Proteins - isolation & purification tau Proteins - metabolism tau aggregation liquid–liquid phase separation Alzheimer's disease phosphorylation
ISSN:	0261-4189, 1460-2075, 1460-2075
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Summary:	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. Synopsis The microtubule binding protein tau can undergo liquid‐liquid phase separation under physiological conditions. Phosphorylated, FTD‐mutant, and Alzheimer's disease brain tau is capable of forming droplets that can initiate the formation of aberrant, aggregated tau “seeds”. LLPS may play a role in different tauopathies. Full‐length human tau can undergo liquid‐liquid phase separation in neurons. In vitro studies show importance of phosphorylation and Frontotemporal Dementia mutations for tau LLPS. AD brain tau is competent of forming droplets. Tau droplets can transition into aggregates. Tau LLPS is a potential mechanism for aggregation initiation in tauopathies. Graphical Abstract An Alzheimer's Disease‐associated tau phase transition from soluble to droplet may exemplify a biophysical mechanism underlying several neurodegenerative diseases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.201798049