Tau protein liquid–liquid phase separation can initiate tau aggregation
By Susanne Wegmann, B. Eftekharzadeh, Katharina Tepper, K. Zoltowska, Rachel E. Bennett, Simon Dujardin, P. Laskowski, Danny MacKenzie, Tarun V Kamath, Caitlin Commins and 10 more. EMBO Journal, 2018
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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.
Subfields: Materials Chemistry, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/370466d42885c31d837010599a9256df23f20221
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Citations in the corpus
- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Peptides containing 2N4R tau microtubule binding repeats or and full-length tau undergo LLPS in solution and cells, respectively [225, 226].”
- Liquid-Liquid Phase Separation in Disease. (2019, background): “Local nucleation of mi- crotubule bundles through tubulin concentration into a condensed Tau phase.”