Ubiquitination of Alzheimer's-related tau protein affects liquid-liquid phase separation in a site- and cofactor-dependent manner

2022 ◽  
Vol 201 ◽  
pp. 173-181
Author(s):  
Francesca Parolini ◽  
Roberto Tira ◽  
Carlo Giorgio Barracchia ◽  
Francesca Munari ◽  
Stefano Capaldi ◽  
...  
2019 ◽  
Vol 294 (29) ◽  
pp. 11054-11059 ◽  
Author(s):  
Solomiia Boyko ◽  
Xu Qi ◽  
Tien-Hao Chen ◽  
Krystyna Surewicz ◽  
Witold K. Surewicz

2018 ◽  
Vol 37 (7) ◽  
Author(s):  
Susanne Wegmann ◽  
Bahareh Eftekharzadeh ◽  
Katharina Tepper ◽  
Katarzyna M Zoltowska ◽  
Rachel E Bennett ◽  
...  

2020 ◽  
Vol 117 (50) ◽  
pp. 31882-31890
Author(s):  
Solomiia Boyko ◽  
Krystyna Surewicz ◽  
Witold K. Surewicz

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.


2020 ◽  
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Yinson Yin ◽  
...  

AbstractAmyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) both in vivo and in vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while independent of aggregation in other cases. It is therefore important to understand the differentiating properties that resolve this apparent conflict. We report on a model system of hydrophobically driven LLPS induced by high salt concentration (LLPS-HS), and compare it to electrostatically driven LLPS represented by tau-RNA/heparin complex coacervation (LLPS-ED). We show that LLPS-HS promotes tau protein dehydration, undergoes maturation and directly leads to canonical tau fibrils, while LLPS-ED is reversible, remains hydrated and does not promote amyloid aggregation. We show that the nature of the interaction driving tau condensation is the differentiating factor between aggregation-prone and aggregation-independent LLPS.


Author(s):  
Xuewei Dong ◽  
Santu Bera ◽  
Qin Qiao ◽  
Yiming Tang ◽  
Zenghui Lao ◽  
...  

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  

Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...


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