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. 2025 Jun 5;85(11):2230-2245.e7.
doi: 10.1016/j.molcel.2025.05.011. Epub 2025 May 28.

Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation

Tapojyoti Das  1 , Fatima K Zaidi  1 , Mina Farag  2 , Kiersten M Ruff  2 , Tharun Selvam Mahendran  3 , Anurag Singh  3 , Xinrui Gui  1 , James Messing  4 , J Paul Taylor  4 , Priya R Banerjee  3 , Rohit V Pappu  5 , Tanja Mittag  6
Affiliations

Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation

Tapojyoti Das et al. Mol Cell. .

Abstract

Stress granules form via co-condensation of RNA-binding proteins (RBPs) containing prion-like low-complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by amyotrophic lateral sclerosis (ALS)-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation, whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.

Keywords: RNP granule; amyotrophic lateral sclerosis; fibril formation; frontotemporal dementia; metastability; phase separation; prion-like domain; sink potential; stress granule; supersaturation.

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Conflict of interest statement

Declaration of interests R.V.P. is a member of the Scientific Advisory Board and a shareholder of Dewpoint Therapeutics. T.M. is a member of the advisory board of Molecular Cell. P.R.B. is a member of the Biophysics Reviews (AIP Publishing) editorial board. The work reported here was not influenced by these affiliations.

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