Oral Presentation 51st Lorne Proteins Conference 2026

Monitor and modulate the pathological aggregation of protein condensates (132715)

Yi Shen 1 , Daniele Vigolo 1 , Dea Ilhamsyah 1 , Tuomas Knowles 2 , David Weitz 3 , Jerelle Joseph 4
  1. University of Sydney, Sydney, NSW, Australia
  2. Chemistry, The University of Cambridge, cambridge, uk
  3. Harvard University, cambridge, MA, United States
  4. Princeton University, Princeton, NJ, United States

Many large molecules in cells can separate into distinct phases, forming biomolecular condensates that organise key biochemical reactions. While these condensates are normally dynamic and liquid-like, under certain conditions they can undergo a transition to a more solid-like state, a process linking both cell functions and disease such as ALS and dementia. The mechanisms driving this transformation remain poorly understood. In our research, we combined microfluidic, optical techniques and computational simulation to study this transition in several protein systems. We discovered that protein condensates do not solidify uniformly; instead, they exhibit coexisting liquid and solid regions, producing structural heterogeneity. Strikingly, this change originates at the condensate boundary, a feature underlies the initial nucleation of harmful aggregates in cells. Furthermore, we found that nucleic acids significantly modulate the protein phase behaviour, echoing the complex cellular environment where DNA/RNA are abundant. To capture these local dynamics, we developed Spatial Dynamic Mapping Microscopy, which revealed that the liquid-to-solid transition begins specifically at the interface between dense and dilute regions. We further established a thermal-cycling platform demonstrating that controlled temperature variations can delay or even reverse pathological protein aggregation. Together, these findings provide high-resolution insight into condensate dynamics and edge-initiated transitions, while also suggesting potential strategies to mitigate aberrant phase transitions associated with disease.

  1. Y. Shen, Biomolecular condensates undergo a generic shear-mediated liquid-to-solid transition. Nat Nanotechnol 15, 841–847 (2020).
  2. T. Li, Functional Biomaterials Derived from Protein Liquid–Liquid Phase Separation and Liquid‐to‐Solid Transition. Advanced Materials 2414703, 1–24 (2025).
  3. A. Garaizar, Aging can transform single-component protein condensates into multiphase architectures. Proc Natl Acad Sci U S A 119, e2119800119 (2022).
  4. Y. Shen, The liquid-to-solid transition of FUS is promoted by the condensate surface. Proceedings of the National Academy of Sciences 120, e2301366120 (2023).
  5. A. Anwar, T. Li, Y. Shen, Thermal Cycling Resets the Irreversible Liquid-to-Solid Transition of Peptide Condensates during Aging. ACS Appl. Mater. Interfaces 17, 38696–38707 (2025).