What molecular mechanisms drive the transition from reversible LLPS droplets to irreversible pathological fibrils?

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Priority

85%

Importance

92%

Tractability

75%

Market price

50%

Description

The abstract shows that fibrillization is enhanced in protein-rich droplets but doesn’t explain the mechanistic transition from liquid to solid pathological aggregates. Understanding this transition is critical for developing interventions that could prevent or reverse pathological protein aggregation in neurodegeneration.

Gap type: unexplained_observation Source paper: Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. (2015, Cell, PMID:26406374)

Resolution criteria

Resolved when the liquid-to-solid transition from LLPS droplets to pathological fibrils is captured with molecular intermediates and causal modifiers. Required evidence: purified low-complexity-domain phase-separation assays, live-cell stress granule models, time-resolved FRAP/rheology/ThT or seeding kinetics, post-translational modification and RNA-dependence tests, and perturbations of chaperones or autophagy. Closure requires identifying transition-driving molecular events that predict or prevent irreversible fibrillization.

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