2020
DOI: 10.1101/2020.07.04.187997
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Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelope

Abstract: AbstractRecent studies show that a single MAPT gene mutation can promote alternative tau misfolding pathways engendering divergent forms of frontotemporal dementia and that under conditions of molecular crowding, the repertoire of tau forms can include liquid-liquid phase separation (LLPS). We show here that following pathogenic seeding, tau condenses on the nuclear envelope (NE) and disrupts nuclear-cytoplasmic transport (NCT). Interestingly, NE fluo… Show more

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Cited by 4 publications
(5 citation statements)
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“…Tau condensation into droplets (complex coacervation) was also observed in the presence of polyanions such as RNA or heparin (17,18). These observations in vitro are partially supported by studies in cells (13,(19)(20)(21)(22)(23)(24), especially within the context of tau interaction with microtubules (21). However, it remains unclear whether tau could undergo LLPS in cells on its own or, rather, its recruitment to membraneless organelles such as stress granules is largely driven by interactions with other proteins and/or RNA.…”
mentioning
confidence: 77%
“…Tau condensation into droplets (complex coacervation) was also observed in the presence of polyanions such as RNA or heparin (17,18). These observations in vitro are partially supported by studies in cells (13,(19)(20)(21)(22)(23)(24), especially within the context of tau interaction with microtubules (21). However, it remains unclear whether tau could undergo LLPS in cells on its own or, rather, its recruitment to membraneless organelles such as stress granules is largely driven by interactions with other proteins and/or RNA.…”
mentioning
confidence: 77%
“…The droplets were able to rapidly recover from photobleaching and fuse with other droplets, confirming they were indeed liquid. Tau condensation also caused nuclear deformation and bubble-like protrusions in the nuclear envelope ( Kang et al, 2020 ). These tau condensates served as sites for fibril nucleation when the droplet grew larger than 3 μm, as detected by Thioflavin S staining.…”
Section: Main Bodymentioning
confidence: 99%
“…This may provide an explanation for the classic neurofibrillary tangles observed around the cell nucleus in tauopathies. Finally, tau condensation also disrupted nuclear trafficking, which eventually led to cell death ( Kang et al, 2020 ).…”
Section: Main Bodymentioning
confidence: 99%
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“…Tau biosensor assays and overexpression of tau in neuronal cultures have substantially expanded our knowledge about tau seeding activity and conformational diversity of misfolded tau protein [ 17 , 26 , 27 , 29 36 ]. However, these seeding assays do not allow the investigation of molecular mechanisms of late synaptic effects.…”
Section: Introductionmentioning
confidence: 99%