Tau protein liquid-liquid phase separation can initiate tau aggregation

Autor: Zhanyun Fan, Tarun V. Kamath, Anthony A. Hyman, Charles R. Vanderburg, J. Paul Taylor, Bahareh Eftekharzadeh, Amandine Molliex, Bradley T. Hyman, Katarzyna Marta Zoltowska, Katharina Tepper, Rachel E. Bennett, Allyson D. Roe, Pawel R. Laskowski, Susanne Wegmann, Amayra Hernández-Vega, Daniel J. Müller, Caitlin Commins, Eckhard Mandelkow, Simon Dujardin, Danny MacKenzie
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
liquid–liquid phase separation
metabolism [Recombinant Proteins]
Physiology
Heterogeneous Nuclear Ribonucleoprotein A1
hnRNPA1 protein
human

Mutant
metabolism [Neurodegenerative Diseases]
Mice
Neuroblastoma
isolation & purification [tau Proteins]
Sequence Analysis
Protein

Sf9 Cells
tau
Cloning
Molecular

Phosphorylation
Aged
80 and over

Neurons
thioflavin T
General Neuroscience
TDP-43 protein
human

aggregation
Brain
Neurodegenerative Diseases
Neurofibrillary Tangles
Articles
Alzheimer's disease
Protein Biosynthesis & Quality Control
Recombinant Proteins
genetics [Recombinant Proteins]
DNA-Binding Proteins
metabolism [Neurofibrillary Tangles]
metabolism [Neurons]
Female
metabolism [DNA-Binding Proteins]
metabolism [Alzheimer Disease]
metabolism [Benzothiazoles]
Liquid-Liquid Extraction
Tau protein
metabolism [Heterogeneous Nuclear Ribonucleoprotein A1]
metabolism [Neuroblastoma]
Mice
Transgenic

tau Proteins
Context (language use)
Biology
Protein Aggregation
Pathological

Biophysical Phenomena
Article
General Biochemistry
Genetics and Molecular Biology

03 medical and health sciences
metabolism [Protein Aggregation
Pathological]

Alzheimer Disease
ddc:570
mental disorders
Escherichia coli
Animals
Humans
Liquid liquid
Amino Acid Sequence
Benzothiazoles
Molecular Biology
General Immunology and Microbiology
metabolism [Amyotrophic Lateral Sclerosis]
chemistry [tau Proteins]
Amyotrophic Lateral Sclerosis
genetics [Escherichia coli]
metabolism [tau Proteins]
Molecular Weight
HEK293 Cells
030104 developmental biology
metabolism [Brain]
Biophysics
biology.protein
Zdroj: EMBO Journal
The EMBO Journal
The EMBO journal 37(7), e98049 (2018). doi:10.15252/embj.201798049
DOI: 10.15252/embj.201798049
Popis: 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.
Databáze: OpenAIRE