Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelope

Kang, Sang Gyun; Han, Zhuang Zhuang; Daude, Nathalie; McNamara, Emily; Wohlgemuth, Serene; Safar, Jiri; Mok, Sue-Ann; Westaway, David

doi:10.1101/2020.07.04.187997

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%

Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

Boyko

Surewicz

2020

Proc. Natl. Acad. Sci. U.S.A.

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One of the hallmarks of Alzheimer’s disease and several other neurodegenerative disorders is the aggregation of tau protein into fibrillar structures. Building on recent reports that tau readily undergoes liquid–liquid phase separation (LLPS), here we explored the relationship between disease-related mutations, LLPS, and tau fibrillation. Our data demonstrate that, in contrast to previous suggestions, pathogenic mutations within the pseudorepeat region do not affect tau441’s propensity to form liquid droplets. LLPS does, however, greatly accelerate formation of fibrillar aggregates, and this effect is especially dramatic for tau441 variants with disease-related mutations. Most important, this study also reveals a previously unrecognized mechanism by which LLPS can regulate the rate of fibrillation in mixtures containing tau isoforms with different aggregation propensities. This regulation results from unique properties of proteins under LLPS conditions, where total concentration of all tau variants in the condensed phase is constant. Therefore, the presence of increasing proportions of the slowly aggregating tau isoform gradually lowers the concentration of the isoform with high aggregation propensity, reducing the rate of its fibrillation. This regulatory mechanism may be of direct relevance to phenotypic variability of tauopathies, as the ratios of fast and slowly aggregating tau isoforms in brain varies substantially in different diseases.

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mentioning

confidence: 77%

Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

Boyko

Surewicz

2020

Proc. Natl. Acad. Sci. U.S.A.

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“…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%

“…Cellular polyanions, such as RNA and microtubules, are known to promote tau phase separation, and early evidence suggests that tau forms a phase-separated gel formed on the surface of anionic membranes ( Majewski et al, 2020 ). Phase-separated tau droplets have been observed surrounding the nuclear membrane, and these droplets may serve as nucleation sites for fibril growth and neurofibrillary tangles ( Kang et al, 2020 ). The role of condensed tau is not yet clear, whether this will serve as a mechanism for reducing pathogenic aggregation, promoting aggregation, or simply concentrating tau at the membrane to promote its native functions.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Tau and Membranes: Interactions That Promote Folding and Condensation

Sallaberry

Voss

Majewski

et al. 2021

Front. Cell Dev. Biol.

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Tau misfolding and assembly is linked to a number of neurodegenerative diseases collectively described as tauopathies, including Alzheimer’s disease (AD) and Parkinson’s disease. Anionic cellular membranes, such as the cytosolic leaflet of the plasma membrane, are sites that concentrate and neutralize tau, primarily due to electrostatic interactions with tau’s microtubule binding repeat domain (RD). In addition to electrostatic interactions with lipids, tau also has interactions with membrane proteins, which are important for tau’s cellular functions. Tau also interacts with lipid tails to facilitate direct translocation across the membrane and can form stable protein-lipid complexes involved in cell-to-cell transport. Concentrated tau monomers at the membrane surface can form reversible condensates, change secondary structures, and induce oligomers, which may eventually undergo irreversible crosslinking and fibril formation. These β-sheet rich tau structures are capable of disrupting membrane organization and are toxic in cell-based assays. Given the evidence for relevant membrane-based tau assembly, we review the emerging hypothesis that polyanionic membranes may serve as a site for phase-separated tau condensation. Membrane-mediated phase separation may have important implications for regulating tau folding/misfolding, and may be a powerful mechanism to spatially direct tau for native membrane-mediated functions.

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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%

Evolving prion-like tau conformers differentially alter postsynaptic proteins in neurons inoculated with distinct isolates of Alzheimer’s disease tau

Hromadkova,

Kim,

Haldiman

et al. 2023

Cell Biosci

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Objectives Although accumulation of misfolded tau species has been shown to predict cognitive decline in patients with Alzheimer’s disease (AD) and other tauopathies but with the remarkable diversity of clinical manifestations, neuropathology profiles, and time courses of disease progression remaining unexplained by current genetic data. We considered the diversity of misfolded tau conformers present in individual AD cases as an underlying driver of the phenotypic variations of AD and progressive loss of synapses. Methods To model the mechanism of tau propagation and synaptic toxicity of distinct tau conformers, we inoculated wild-type primary mouse neurons with structurally characterized Sarkosyl-insoluble tau isolates from the frontal cortex of six AD cases and monitored the impact for fourteen days. We analyzed the accumulation rate, tau isoform ratio, and conformational characteristics of de novo-induced tau aggregates with conformationally sensitive immunoassays, and the dynamics of synapse formation, maintenance, and their loss using a panel of pre-and post-synaptic markers. Results At the same concentrations of tau, the different AD tau isolates induced accumulation of misfolded predominantly 4-repeat tau aggregates at different rates in mature neurons, and demonstrated distinct conformational characteristics corresponding to the original AD brain tau. The time-course of the formation of misfolded tau aggregates and colocalization correlated with significant loss of synapses in tau-inoculated cell cultures and the reduction of synaptic connections implicated the disruption of postsynaptic compartment as an early event. Conclusions The data obtained with mature neurons expressing physiological levels and adult isoforms of tau protein demonstrate markedly different time courses of endogenous tau misfolding and differential patterns of post-synaptic alterations. These and previous biophysical data argue for an ensemble of various misfolded tau aggregates in individual AD brains and template propagation of their homologous conformations in neurons with different rates and primarily postsynaptic interactors. Modeling tau aggregation in mature differentiated neurons provides a platform for investigating divergent molecular mechanisms of tau strain propagation and for identifying common structural features of misfolded tau and critical interactors for new therapeutic targets and approaches in AD.

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Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelope

Cited by 4 publications

References 71 publications

Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

Regulatory mechanisms of tau protein fibrillation under the conditions of liquid–liquid phase separation

Tau and Membranes: Interactions That Promote Folding and Condensation

Evolving prion-like tau conformers differentially alter postsynaptic proteins in neurons inoculated with distinct isolates of Alzheimer’s disease tau

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