Biomolecular condensation of the microtubule-associated protein tau

Ukmar‐Godec, Tina; Wegmann, Susanne; Zweckstetter, Markus

doi:10.1016/j.semcdb.2019.06.007

Cited by 32 publications

(21 citation statements)

References 181 publications

(295 reference statements)

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“…In agreement with the importance of charge–charge interactions, tau LLPS in the presence of RNA is insensitive to 1,6‐hexanediol, an aliphatic alcohol that can dissolve droplets held together by hydrophobic interactions 157 . Additionally, conditions in which charge neutralization occurs promote tau/RNA LLPS 121,135,142 . Several different tau constructs/fragments can therefore undergo RNA‐induced LLPS when the tau/RNA molar ratio is optimized 121,135,142 …”

Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 63%

“…The importance of electrostatic interactions for tau LLPS is further supported by the observation that LLPS occurs spontaneously when the N‐terminal truncated part (tauΔ1‐117) is mixed with the negatively charged tauΔ118‐441 truncation. Due to the net negative charge, the tau N‐terminal region is likely to provide electrostatic contributions to LLPS as evinced by studies on the full‐length protein and its variants 38,39,135 . Turbidity measurements combined with fluorescence microscopy showed that the tau construct, K25, comprising only the N‐terminal projection domain and proline‐rich domain, forms liquid‐like droplets 123,125 .…”

Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

“…The affinity of tau for RNA was estimated as ~500 nM 121 . RNA efficiently induces and promotes tau LLPS in vitro 120,121,135 (Figure 3). Because tau and RNA molecules are positively and negatively charged, respectively, the tau/RNA interaction has a strong electrostatic component.…”

Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 99%

“…Additionally, conditions in which charge neutralization occurs promote tau/RNA LLPS 121,135,142 . Several different tau constructs/fragments can therefore undergo RNA‐induced LLPS when the tau/RNA molar ratio is optimized 121,135,142 …”

Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 99%

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Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

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Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase‐separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid‐like membrane‐less compartments. However, aberrant phase transitions into gel‐like or solid‐like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule‐associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid‐to‐solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one‐component and complex multi‐component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length‐ and time‐scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.

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Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 63%

Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 99%

Section: Tau Condensation: From Cofactors To Post‐translational Modificationsmentioning

confidence: 99%

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Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

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“…Phase-separated tau is thought to be the main template for aggregation [100][101][102][103], as these tau droplets transition from a gel-like into an aggregate state of lower energy and grow into non-spherical solid aggregates. There might also be a physiological role for tau LLPS that may include regulation of stress granule formation and nucleation of microtubule polymerization [104][105][106]. There are still many unanswered questions on what drives tau LLPS and what non-tau molecular factors are involved.…”

Section: Tau Misfolding and Phase Transitionmentioning

confidence: 99%

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

Silva

Haggarty

2020

IJMS

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Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed.

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Ultrasmall Gold Nanoparticles as Clients of Biomolecular Condensates

Viola

Floriani

Barracchia

et al. 2023

Chemistry A European J

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Liquid‐liquid phase separation (LLPS) of biopolymers to form condensates is a widespread phenomenon in living cells. Agents that target or alter condensation can help uncover elusive physiological and pathological mechanisms. Owing to their unique material properties and modes of interaction with biomolecules, nanoparticles represent attractive condensate‐targeting agents.Our work focused on elucidating the interaction between ultrasmall gold nanoparticles (usGNPs) and diverse types of condensates of tau, a representative phase‐separating protein associated with neurodegenerative disorders. usGNPs attract considerable interest in the biomedical community due to unique features, including emergent optical properties and good cell penetration. We explored the interaction of usGNPs with reconstituted self‐condensates of tau, two‐component tau/polyanion and three‐component tau/RNA/alpha‐synuclein coacervates. The usGNPs were found to concentrate into condensed liquid droplets, consistent with the formation of dynamic client (nanoparticle) ‐ scaffold (tau) interactions, and were observable thanks to their intrinsic luminescence. Furthermore, usGNPs were capable to promote LLPS of a protein domain which is unable to phase separate on its own.Our study demonstrates the ability of usGNPs to interact with and illuminate protein condensates. We anticipate that nanoparticles will have broad applicability as nanotracers to interrogate phase separation, and as nanoactuators controlling the formation and dissolution of condensates.

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Biomolecular condensation of the microtubule-associated protein tau

Cited by 32 publications

References 181 publications

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

Ultrasmall Gold Nanoparticles as Clients of Biomolecular Condensates

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