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Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion

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  • Aishwarya Agarwal

    (Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali)

  • Lisha Arora

    (Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali)

  • Sandeep K. Rai

    (Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali)

  • Anamika Avni

    (Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali)

  • Samrat Mukhopadhyay

    (Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali
    Indian Institute of Science Education and Research (IISER) Mohali)

Abstract

Biomolecular condensation via liquid-liquid phase separation of proteins and nucleic acids is associated with a range of critical cellular functions and neurodegenerative diseases. Here, we demonstrate that complex coacervation of the prion protein and α-synuclein within narrow stoichiometry results in the formation of highly dynamic, reversible, thermo-responsive liquid droplets via domain-specific electrostatic interactions between the positively-charged intrinsically disordered N-terminal segment of prion and the acidic C-terminal tail of α-synuclein. The addition of RNA to these coacervates yields multiphasic, vesicle-like, hollow condensates. Picosecond time-resolved measurements revealed the presence of transient electrostatic nanoclusters that are stable on the nanosecond timescale and can undergo breaking-and-making of interactions on slower timescales giving rise to a liquid-like behavior in the mesoscopic regime. The liquid-to-solid transition drives a rapid conversion of complex coacervates into heterotypic amyloids. Our results suggest that synergistic prion-α-synuclein interactions within condensates provide mechanistic underpinnings of their physiological role and overlapping neuropathological features.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28797-5
    DOI: 10.1038/s41467-022-28797-5
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    References listed on IDEAS

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    1. Taranpreet Kaur & Muralikrishna Raju & Ibraheem Alshareedah & Richoo B. Davis & Davit A. Potoyan & Priya R. Banerjee, 2021. "Sequence-encoded and composition-dependent protein-RNA interactions control multiphasic condensate morphologies," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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    1. Agustín Mangiarotti & Nannan Chen & Ziliang Zhao & Reinhard Lipowsky & Rumiana Dimova, 2023. "Wetting and complex remodeling of membranes by biomolecular condensates," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Ashish Joshi & Anuja Walimbe & Anamika Avni & Sandeep K. Rai & Lisha Arora & Snehasis Sarkar & Samrat Mukhopadhyay, 2023. "Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Agustín Mangiarotti & Macarena Siri & Nicky W. Tam & Ziliang Zhao & Leonel Malacrida & Rumiana Dimova, 2023. "Biomolecular condensates modulate membrane lipid packing and hydration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Jing Tao & Yanping Zeng & Bin Dai & Yin Liu & Xiaohan Pan & Li-Qiang Wang & Jie Chen & Yu Zhou & Zuneng Lu & Liwei Xie & Yi Liang, 2023. "Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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