2025-05-30 ワシントン大学セントルイス校
<関連情報>
- https://hopecenter.wustl.edu/research-untangles-role-of-stress-granules-in-neurodegenerative-disease/
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00416-2
アミロイド線維形成におけるコンデンセートの調整可能な準安定性が二重の役割を調和させる Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation
Tapojyoti Das ∙ Fatima K. Zaidi ∙ Mina Farag ∙ … ∙ Priya R. Banerjee ∙ Rohit V. Pappu ∙ Tanja Mittag
Molecular Cell Published:May 28, 2025
DOI:https://doi.org/10.1016/j.molcel.2025.05.011
Graphical abstract
Highlights
- Condensates and fibrils of A1-LCD are formed by distinct and separable interactions
- Interiors of metastable condensates act as sinks and suppress fibril formation
- Pathogenic mutations weaken condensate metastability and enhance fibril formation
- Designed mutations that enhance metastability can rescue a pathogenic phenotype
Summary
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.
