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Liquid-liquid phase separation induces pathogenic tau conformations in vitro

Author

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  • Nicholas M. Kanaan

    (Michigan State University
    Michigan State University
    Mercy Health Saint Mary’s)

  • Chelsey Hamel

    (Michigan State University)

  • Tessa Grabinski

    (Michigan State University)

  • Benjamin Combs

    (Michigan State University)

Abstract

Formation of membrane-less organelles via liquid-liquid phase separation is one way cells meet the biological requirement for spatiotemporal regulation of cellular components and reactions. Recently, tau, a protein known for its involvement in Alzheimer’s disease and other tauopathies, was found to undergo liquid–liquid phase separation making it one of several proteins associated with neurodegenerative diseases to do so. Here, we demonstrate that tau forms dynamic liquid droplets in vitro at physiological protein levels upon molecular crowding in buffers that resemble physiological conditions. Tau droplet formation is significantly enhanced by disease-associated modifications, including the AT8 phospho-epitope and the P301L tau mutation linked to an inherited tauopathy. Moreover, tau droplet dynamics are significantly reduced by these modified forms of tau. Extended phase separation promoted a time-dependent adoption of toxic conformations and oligomerization, but not filamentous aggregation. P301L tau protein showed the greatest oligomer formation following extended phase separation. These findings suggest that phase separation of tau may facilitate the formation of non-filamentous pathogenic tau conformations.

Suggested Citation

  • Nicholas M. Kanaan & Chelsey Hamel & Tessa Grabinski & Benjamin Combs, 2020. "Liquid-liquid phase separation induces pathogenic tau conformations in vitro," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16580-3
    DOI: 10.1038/s41467-020-16580-3
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    Cited by:

    1. Pablo Gracia & David Polanco & Jorge Tarancón-Díez & Ilenia Serra & Maruan Bracci & Javier Oroz & Douglas V. Laurents & Inés García & Nunilo Cremades, 2022. "Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Qin Peng & Ziliang Huang & Kun Sun & Yahan Liu & Chi Woo Yoon & Reed E. S. Harrison & Danielle L. Schmitt & Linshan Zhu & Yiqian Wu & Ipek Tasan & Huimin Zhao & Jin Zhang & Sheng Zhong & Shu Chien & Y, 2022. "Engineering inducible biomolecular assemblies for genome imaging and manipulation in living cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Aishwarya Agarwal & Lisha Arora & Sandeep K. Rai & Anamika Avni & Samrat Mukhopadhyay, 2022. "Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Yongqi Huang & Jitao Wen & Lisa-Marie Ramirez & Eymen Gümüşdil & Pravin Pokhrel & Viet H. Man & Haiqiong Ye & Yue Han & Yunfei Liu & Ping Li & Zhengding Su & Junmei Wang & Hanbin Mao & Markus Zweckste, 2023. "Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Shanley F. Longfield & Mahdie Mollazade & Tristan P. Wallis & Rachel S. Gormal & Merja Joensuu & Jesse R. Wark & Ashley J. Waardenberg & Christopher Small & Mark E. Graham & Frédéric A. Meunier & Ramó, 2023. "Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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