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

Aishwarya Agarwal, Lisha Arora, Sandeep K. Rai, Anamika Avni and Samrat Mukhopadhyay ()
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Aishwarya Agarwal: Indian Institute of Science Education and Research (IISER) Mohali
Lisha Arora: Indian Institute of Science Education and Research (IISER) Mohali
Sandeep K. Rai: Indian Institute of Science Education and Research (IISER) Mohali
Anamika Avni: Indian Institute of Science Education and Research (IISER) Mohali
Samrat Mukhopadhyay: Indian Institute of Science Education and Research (IISER) Mohali

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28797-5

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