Tau protein liquid–liquid phase separation can initiate tau aggregation
Copyright policy )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 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.
The EMBO Journal, 37 (7)
ISSN:0261-4189
ISSN:1460-2075
- ETH Zurich Switzerland
- Massachusetts General Hospital United States
- German Center for Neurodegenerative Diseases Germany
- Max Planck Society Germany
- Helmholtz Association of German Research Centres Germany
liquid–liquid phase separation, Physiology, metabolism [Recombinant Proteins], Heterogeneous Nuclear Ribonucleoprotein A1, hnRNPA1 protein, human, metabolism [Neurodegenerative Diseases], Mice, Neuroblastoma, isolation & purification [tau Proteins], Sequence Analysis, Protein, Sf9 Cells, tau, Phosphorylation, Cloning, Molecular, Neurons, Aged, 80 and over, thioflavin T, phosphorylation, TDP-43 protein, human, aggregation, Brain, Neurodegenerative Diseases, Neurofibrillary Tangles, Articles, Protein Biosynthesis & Quality Control, Alzheimer's disease, Recombinant Proteins, genetics [Recombinant Proteins], DNA-Binding Proteins, aggregation; Alzheimer’s disease; liquid–liquid phase separation; phosphorylation; tau, metabolism [Neurofibrillary Tangles], metabolism [Neurons], Female, metabolism [DNA-Binding Proteins], Alzheimer’s disease, metabolism [Alzheimer Disease], 570, metabolism [Benzothiazoles], Liquid-Liquid Extraction, metabolism [Heterogeneous Nuclear Ribonucleoprotein A1], metabolism [Neuroblastoma], tau Proteins, Mice, Transgenic, Protein Aggregation, Pathological, Article, Biophysical Phenomena, metabolism [Protein Aggregation, Pathological], Alzheimer Disease, Escherichia coli, Animals, Humans, Amino Acid Sequence, Benzothiazoles, metabolism [Amyotrophic Lateral Sclerosis], chemistry [tau Proteins], Amyotrophic Lateral Sclerosis, genetics [Escherichia coli], 540, metabolism [tau Proteins], Molecular Weight, HEK293 Cells, metabolism [Brain], ddc: ddc:570
liquid–liquid phase separation, Physiology, metabolism [Recombinant Proteins], Heterogeneous Nuclear Ribonucleoprotein A1, hnRNPA1 protein, human, metabolism [Neurodegenerative Diseases], Mice, Neuroblastoma, isolation & purification [tau Proteins], Sequence Analysis, Protein, Sf9 Cells, tau, Phosphorylation, Cloning, Molecular, Neurons, Aged, 80 and over, thioflavin T, phosphorylation, TDP-43 protein, human, aggregation, Brain, Neurodegenerative Diseases, Neurofibrillary Tangles, Articles, Protein Biosynthesis & Quality Control, Alzheimer's disease, Recombinant Proteins, genetics [Recombinant Proteins], DNA-Binding Proteins, aggregation; Alzheimer’s disease; liquid–liquid phase separation; phosphorylation; tau, metabolism [Neurofibrillary Tangles], metabolism [Neurons], Female, metabolism [DNA-Binding Proteins], Alzheimer’s disease, metabolism [Alzheimer Disease], 570, metabolism [Benzothiazoles], Liquid-Liquid Extraction, metabolism [Heterogeneous Nuclear Ribonucleoprotein A1], metabolism [Neuroblastoma], tau Proteins, Mice, Transgenic, Protein Aggregation, Pathological, Article, Biophysical Phenomena, metabolism [Protein Aggregation, Pathological], Alzheimer Disease, Escherichia coli, Animals, Humans, Amino Acid Sequence, Benzothiazoles, metabolism [Amyotrophic Lateral Sclerosis], chemistry [tau Proteins], Amyotrophic Lateral Sclerosis, genetics [Escherichia coli], 540, metabolism [tau Proteins], Molecular Weight, HEK293 Cells, metabolism [Brain], ddc: ddc:570
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