Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

Yanxian Lin; Yann Fichou; Andrew P. Longhini; Luana C. Llanes; Pengyi Yin; Guillermo C. Bazan; Kenneth S. Kosik; Songi Han

doi:10.1016/j.jmb.2020.166731

Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

Yanxian Lin, Yann Fichou, Andrew P. Longhini, Luana C. Llanes, Pengyi Yin, Guillermo C. Bazan, Kenneth S. Kosik, Songi Han^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

Amyloid 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 being 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 a differentiating factor between aggregation-prone and aggregation-independent LLPS.

Original language	English (US)
Article number	166731
Journal	Journal of Molecular Biology
Volume	433
Issue number	2
DOIs	https://doi.org/10.1016/j.jmb.2020.166731
State	Published - Jan 22 2021

Funding

The authors acknowledge support for the studies of LLPS mechanisms from the National Institutes of Health (NIH) by grant R01AG056058 and support of the Tau consortium of the Rainwater foundation for SH and KSK to study the effect of LLPS on tau pathology. Studies of protein surface hydration properties were supported by the NIH MIRA grant R35GM136411 awarded to SH. We acknowledge support for the synthesis of BODIPY-NHS dye from the National Science Foundation (DMR-1922042). We acknowledge the use of the NRI-MCDB Microscopy Facility and the Resonant Scanning Confocal supported by NSF MRI grant DBI-1625770 at UC, Santa Barbara. We acknowledge the use of the MRL Shared Experimental Facilities which are supported by the MRSEC Program of the NSF under Award No. DMR 1720256; a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org)

Keywords

amyloid aggregation
electron paramagnetic resonance
hydrophobic interaction
liquid–liquid phase separation
tau

ASJC Scopus subject areas

Molecular Biology
Biophysics
Structural Biology

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title = "Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau",

abstract = "Amyloid 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 being 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 a differentiating factor between aggregation-prone and aggregation-independent LLPS.",

keywords = "amyloid aggregation, electron paramagnetic resonance, hydrophobic interaction, liquid–liquid phase separation, tau",

author = "Yanxian Lin and Yann Fichou and Longhini, {Andrew P.} and Llanes, {Luana C.} and Pengyi Yin and Bazan, {Guillermo C.} and Kosik, {Kenneth S.} and Songi Han",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2021",

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doi = "10.1016/j.jmb.2020.166731",

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AU - Lin, Yanxian

AU - Fichou, Yann

AU - Longhini, Andrew P.

AU - Llanes, Luana C.

AU - Yin, Pengyi

AU - Bazan, Guillermo C.

AU - Kosik, Kenneth S.

AU - Han, Songi

PY - 2021/1/22

Y1 - 2021/1/22

N2 - Amyloid 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 being 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 a differentiating factor between aggregation-prone and aggregation-independent LLPS.

AB - Amyloid 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 being 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 a differentiating factor between aggregation-prone and aggregation-independent LLPS.

KW - amyloid aggregation

KW - electron paramagnetic resonance

KW - hydrophobic interaction

KW - liquid–liquid phase separation

KW - tau

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Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

Abstract

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ASJC Scopus subject areas

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